Modulators of cellular adhesion

ABSTRACT

The present invention provides compounds having formula (I): 
                         
and pharmaceutically acceptable derivatives thereof, wherein R 1 -R 4 , n, p, A, B, D, E, L and AR 1  are as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of disorders mediated by the CD11/CD18 family of cellular adhesion molecules (e.g., LFA-1).

This application claims priority under 35 U.S.C. §120 as a continuationof U.S. application Ser. No. 12/537,147, filed Aug. 6, 2009 (pending),which is a continuation of U.S. application Ser. No. 11/934,049, filedNov. 1, 2007, issued as U.S. Pat. No. 7,790,743, which is a divisionalapplication of U.S. application Ser. No. 10/982,463, filed Nov. 5, 2004,issued as U.S. Pat. No. 7,314,938, which claims the benefit under 35U.S.C. §119(e) of U.S. Provisional Application Ser. Nos. 60/560,517,filed Apr. 8, 2004, and 60/517,535, filed Nov. 5, 2003; the contents ofeach application are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Research conducted over the last decade has helped elucidate themolecular events attending cell-cell interactions in the body,especially those events involved in the movement and activation of cellsin the immune system. See generally, Springer, T. Nature, 1990, 346,425-434. Cell surface proteins, and especially the Cellular AdhesionMolecules (“CAMs”) and “leukointegrins”, including LFA-1, MAC-1 andgp150.95 (referred to as CD18/CD11a, CD18/CD11b, and CD18/CD11c,respectively) have correspondingly been the subject of pharmaceuticalresearch and development having as its goal the intervention in theprocesses of leukocyte extravasation to sites of injury and leukocytemovement to distinct targets. For example, it is presently believed thatprior to the leukocyte extravasation, which is a mandatory component ofthe inflammatory response, activation of integrins constitutivelyexpressed on leukocytes occurs and is followed by a tightligand/receptor interaction between integrins (e.g., LFA-1) and one orseveral distinct intercellular adhesion molecules (ICAMs) designatedICAM-1, ICAM-2, ICAM-3 or ICAM-4 which are expressed on blood vesselendothelial cell surfaces and on other leukocytes. The interaction ofthe CAMs with the leukointegrins is a vital step in the normalfunctioning of the immune system. It is believed that immune processessuch as antigen presentation, T-cell mediated cytotoxicity and leukocyteextravasation all require cellular adhesion mediated by ICAMsinteracting with the leukointegrins. See generally Kishimoto, T. K.;Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.;Springer, T. Current Biology, 1994, 4, 506-532.

Clearly, because of the role that the interaction of the CAMs and theleukointegrins plays in the immune response, it would be desirable tomodulate these specific interactions to achieve a desired therapeuticresult (e.g., inhibition of the interaction in the event of anoveractive immune response). Significantly, it has been demonstratedthat the antagonism of the interaction between the CAMs and theleukointegrins can be realized by agents directed against eithercomponent. Specifically, blocking of the CAMs, such as for exampleICAM-1, or the leukointegrins, such as for example LFA-1, by antibodiesdirected against either or both of these molecules effectively inhibitsinflammatory responses. In vitro models of inflammation and immuneresponse inhibited by antibodies to CAMs or leukointegrins includeantigen or mitogen-induced lymphocyte proliferation, homotypicaggregation of lymphocytes, T-cell mediated cytolysis andantigen-specific induced tolerance. The relevance of the in vitrostudies are supported by in vivo studies with antibodies directedagainst ICAM-1 or LFA-1. For example, antibodies directed against LFA-1can prevent thyroid graft rejection and prolong heart allograft survivalin mice (Gorski, A.; Immunology Today, 1994, 15, 251-255). Of greatersignificance, antibodies directed against ICAM-1 have shown efficacy invivo as anti-inflammatory agents in human diseases such as renalallograft rejection and rheumatoid arthritis (Rothlein, R. R.;Scharschmidt, L., in: Adhesion Molecules; Wegner, C. D., Ed.; 1994,1-38, Cosimi, C. B.; et al., J. ImmunoL. 1990, 144, 4604-4612 andKavanaugh, A.; et al., Arthritis Rheum. 1994, 37, 992-1004) andantibodies directed against LFA-1 have demonstrated immunosuppressiveeffects in bone marrow transplantation and in the prevention of earlyrejection of renal allografts (Fischer, A.; et al., Lancet, 1989, 2,1058-1060 and Le Mauff, B.; et al., Transplantation, 1991, 52, 291-295).

As described above, the use of anti-LFA-1 or anti-ICAM-1 antibodies toantagonize this interaction has been investigated. Additionally, the useof LFA-1 or ICAM-1 peptides, fragments or peptide antagonists (see, forexample, U.S. Pat. Nos. 5,149,780, 5,288,854, 5,340,800, 5,424,399,5,470,953, Published PCT applications WO 90/03400, WO90/13316,WO90/10652, WO91/19511, WO92/03473, WO94/11400, WO95/28170, JP4193895,EP314863, EP362526, EP362531), and small molecule antagonists have beeninvestigated. For example, several small molecules have been describedin the literature which affect the interaction of CAMs andleukointegrins. A natural product isolated from the root of Trichiliarubra was found to be inhibitory in an in vitro cell binding assay(Musza, L. L.; et al., Tetrahedron, 1994, 50, 11369-11378). One seriesof molecules (Boschelli, D. H.; et al., J. Med. Chem. 1994, 37, 717 andBoschelli, D. H.; et al., J. Med. Chem. 1995, 38, 4597-4614) was foundto be orally active in a reverse passive Arthus reaction, an inducedmodel of inflammation that is characterized by neutrophil accumulation(Chang, Y. H.; et al., Eur. J. Pharmacol. 1992, 69, 155-164). Anotherseries of molecules was also found to be orally active in a delayed typehypersensitivity reaction in rats (Sanfilippo, P. J.; et al., J. Med.Chem. 1995, 38, 1057-1059). All of these molecules appear to actnonspecifically, either by inhibiting the transcription of ICAM-1 alongwith other proteins or act intracellularly to inhibit the activation ofthe leukointegrins by an unknown mechanism, and none appear to directlyantagonize the interaction of the CAMs with the leukointegrins.

Clearly, although several classes of compounds have been investigatedfor therapeutic use, there remains a need for the development of noveltherapeutics that are capable of modulating interactions between CAMsand leukointegrins. In particular, it would be desirable to developtherapeutics capable of selectively targeting (preferably inhibiting)the interaction between LFA-1 and ICAM-1 that would be useful as atherapeutic agent for immune and/or inflammatory disorders.

SUMMARY OF THE INVENTION

As discussed above, there remains a need for the development of noveltherapeutics that are capable of modulating interactions between CAMsand leukointegrins. The present invention provides novel compounds ofgeneral formula (I),

and pharmaceutical compositions thereof, as described generally and insubclasses herein, which compounds are useful as modulators of theCD11/CD18 family of cellular adhesion molecules. Thus these compoundsare useful, for example, for the treatment of various LFA-1-relateddisorders including immune and/or inflammatory disorders.

In yet another aspect, the present invention provides methods fortreating any disorder mediated through the CD11/CD18 family of cellularadhesion molecules comprising administering to a subject in need thereofa therapeutically effective amount of a compound of the invention.

DEFINITIONS

The term “aliphatic”, as used herein, includes both saturated andunsaturated, straight chain (i.e., unbranched) or branched aliphatichydrocarbons, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “aliphatic” is intended herein to include, but is not limitedto, alkyl, alkenyl, alkynyl moieties. Thus, as used herein, the term“alkyl” includes straight and branched alkyl groups. An analogousconvention applies to other generic terms such as “alkenyl”, “alkynyl”and the like. Furthermore, as used herein, the terms “alkyl”, “alkenyl”,“alkynyl” and the like encompass both substituted and unsubstitutedgroups. In certain embodiments, as used herein, “lower alkyl” is used toindicate those alkyl groups (substituted, unsubstituted, branched orunbranched) having about 1-6 carbon atoms.

In certain embodiments, the alkyl, alkenyl and alkynyl groups employedin the invention contain about 1-20 aliphatic carbon atoms. In certainother embodiments, the alkyl, alkenyl, and alkynyl groups employed inthe invention contain about 1-10 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain about 1-8 aliphatic carbon atoms. In still otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain about 1-6 aliphatic carbon atoms. In yet otherembodiments, the alkyl, alkenyl, and alkynyl groups employed in theinvention contain about 1-4 carbon atoms. Illustrative aliphatic groupsthus include, but are not limited to, for example, methyl, ethyl,n-propyl, isopropyl, allyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, sec-pentyl, isopentyl, tert-pentyl, n-hexyl, sec-hexyl,moieties and the like, which again, may bear one or more substituents.Alkenyl groups include, but are not limited to, for example, ethenyl,propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like. Representativealkynyl groups include, but are not limited to, ethynyl, 2-propynyl(propargyl), 1-propynyl and the like.

The term “alicyclic”, as used herein, refers to compounds which combinethe properties of aliphatic and cyclic compounds and include but are notlimited to monocyclic, or polycyclic aliphatic hydrocarbons and bridgedcycloalkyl compounds, which are optionally substituted with one or morefunctional groups. As will be appreciated by one of ordinary skill inthe art, “alicyclic” is intended herein to include, but is not limitedto, cycloalkyl, cycloalkenyl, and cycloalkynyl moieties, which areoptionally substituted with one or more functional groups. Illustrativealicyclic groups thus include, but are not limited to, for example,cyclopropyl, —CH₂-cyclopropyl, cyclobutyl, —CH₂-cyclobutyl, cyclopentyl,—CH₂-cyclopentyl, cyclohexyl, —CH₂-cyclohexyl, cyclohexenylethyl,cyclohexanylethyl, norborbyl moieties and the like, which again, maybear one or more substituents.

The term “alkoxy” or “alkyloxy”, as used herein refers to a saturated(i.e., O-alkyl) or unsaturated (i.e., O-alkenyl and O-alkynyl) groupattached to the parent molecular moiety through an oxygen atom. Incertain embodiments, the alkyl group contains about 1-20 aliphaticcarbon atoms. In certain other embodiments, the alkyl group containsabout 1-10 aliphatic carbon atoms. In yet other embodiments, the alkylgroup employed in the invention contains about 1-8 aliphatic carbonatoms. In still other embodiments, the alkyl group contains about 1-6aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains about 1-4 aliphatic carbon atoms. Examples of alkoxy, includebut are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,i-butoxy, sec-butoxy, tert-butoxy, neopentoxy, n-hexoxy and the like.

The term “thioalkyl” as used herein refers to a saturated (i.e.,S-alkyl) or unsaturated (i.e., S-alkenyl and S-alkynyl) group attachedto the parent molecular moiety through a sulfur atom. In certainembodiments, the alkyl group contains about 1-20 aliphatic carbon atoms.In certain other embodiments, the alkyl group contains about 1-10aliphatic carbon atoms. In yet other embodiments, the alkyl groupemployed in the invention contains about 1-8 aliphatic carbon atoms. Instill other embodiments, the alkyl group contains about 1-6 aliphaticcarbon atoms. In yet other embodiments, the alkyl group contains about1-4 aliphatic carbon atoms. Examples of thioalkyl include, but are notlimited to, methylthio, ethylthio, propylthio, isopropylthio,n-butylthio, and the like.

The term “alkylamino” refers to a group having the structure —NHR′wherein R′ is alkyl, as defined herein. The term “aminoalkyl” refers toa group having the structure NH₂R′—, wherein R′ is alkyl, as definedherein. In certain embodiments, the alkyl group contains about 1-20aliphatic carbon atoms. In certain other embodiments, the alkyl groupcontains about 1-10 aliphatic carbon atoms. In yet other embodiments,the alkyl group employed in the invention contains about 1-8 aliphaticcarbon atoms. In still other embodiments, the alkyl group contains about1-6 aliphatic carbon atoms. In yet other embodiments, the alkyl groupcontains about 1-4 aliphatic carbon atoms. Examples of alkylaminoinclude, but are not limited to, methylamino, ethylamino,iso-propylamino and the like.

Some examples of substituents of the above-described aliphatic (andother) moieties of compounds of the invention include, but are notlimited to aliphatic; alicyclic; heteroaliphatic; heterocyclic;aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl orheteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aryl or heteroaryl substituents described above andherein may be substituted or unsubstituted. Additional examples ofgenerally applicable substituents are illustrated by the specificembodiments shown in the Examples that are described herein.

In general, the term “aromatic moiety”, as used herein, refers to astable mono- or polycyclic, unsaturated moiety having preferably 3-14carbon atoms, each of which may be substituted or unsubstituted. Incertain embodiments, the term “aromatic moiety” refers to a planar ringhaving p-orbitals perpendicular to the plane of the ring at each ringatom and satisfying the Huckel rule where the number of pi electrons inthe ring is (4n+2) wherein n is an integer. A mono- or polycyclic,unsaturated moiety that does not satisfy one or all of these criteriafor aromaticity is defined herein as “non-aromatic”, and is encompassedby the term “alicyclic”.

In general, the term “heteroaromatic moiety”, as used herein, refers toa stable mono- or polycyclic, unsaturated moiety having preferably 3-14carbon atoms, each of which may be substituted or unsubstituted; andcomprising at least one heteroatom selected from O, S and N within thering (i.e., in place of a ring carbon atom). In certain embodiments, theterm “heteroaromatic moiety” refers to a planar ring comprising at leastone heteroatom, having p-orbitals perpendicular to the plane of the ringat each ring atom, and satisfying the Huckel rule where the number of pielectrons in the ring is (4n+2) wherein n is an integer.

It will also be appreciated that aromatic and heteroaromatic moieties,as defined herein may be attached via an alkyl or heteroalkyl moiety andthus also include -(alkyl)aromatic, -(heteroalkyl)aromatic,-(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic moieties.Thus, as used herein, the phrases “aromatic or heteroaromatic moieties”and “aromatic, heteroaromatic, -(alkyl)aromatic, -(heteroalkyl)aromatic,-(heteroalkyl)heteroaromatic, and -(heteroalkyl)heteroaromatic” areinterchangeable. Substituents include, but are not limited to, any ofthe previously mentioned substituents, i.e., the substituents recitedfor aliphatic moieties, or for other moieties as disclosed herein,resulting in the formation of a stable compound.

The term “aryl”, as used herein, does not differ significantly from thecommon meaning of the term in the art, and refers to an unsaturatedcyclic moiety comprising at least one aromatic ring. In certainembodiments, “aryl” refers to a mono- or bicyclic carbocyclic ringsystem having one or two aromatic rings including, but not limited to,phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The term “heteroaryl”, as used herein, does not differ significantlyfrom the common meaning of the term in the art, and refers to a cyclicaromatic radical having from five to ten ring atoms of which one ringatom is selected from S, O and N; zero, one or two ring atoms areadditional heteroatoms independently selected from S, O and N; and theremaining ring atoms are carbon, the radical being joined to the rest ofthe molecule via any of the ring atoms, such as, for example, pyridyl,pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl,oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl,quinolinyl, isoquinolinyl, and the like.

It will be appreciated that aryl and heteroaryl groups (includingbicyclic aryl groups) can be unsubstituted or substituted, whereinsubstitution includes replacement of one or more of the hydrogen atomsthereon independently with any one or more of the following moietiesincluding, but not limited to: aliphatic; alicyclic; heteroaliphatic;heterocyclic; aromatic; heteroaromatic; aryl; heteroaryl; alkylaryl;heteroalkylaryl; alkylheteroaryl; heteroalkylheteroaryl; alkoxy;aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO₂; —CN; —CF₃;—CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x);—CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R_(x); —OCON(R_(x))₂;—N(R_(x))₂; —S(O)R_(x); —S(O)₂R_(x); —NR_(x)(CO)R_(x) wherein eachoccurrence of R_(x) independently includes, but is not limited to,aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic,heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl, heteroaryl,-(alkyl)aryl or -(alkyl)heteroaryl substituents described above andherein may be substituted or unsubstituted. Additionally, it will beappreciated, that any two adjacent groups taken together may represent a4, 5, 6, or 7-membered substituted or unsubstituted alicyclic orheterocyclic moiety. Additional examples of generally applicablesubstituents are illustrated by the specific embodiments shown in theExamples that are described herein.

The term “cycloalkyl”, as used herein, refers specifically to groupshaving three to seven, preferably three to ten carbon atoms. Suitablecycloalkyls include, but are not limited to cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and the like, which, as in the caseof aliphatic, alicyclic, heteroaliphatic or heterocyclic moieties, mayoptionally be substituted with substituents including, but not limitedto aliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;heteroaromatic; aryl; heteroaryl; alkylaryl; heteroalkylaryl;alkylheteroaryl; heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy;heteroaryloxy; alkylthio; arylthio; heteroalkylthio; heteroarylthio; F;Cl; Br; I; —OH; —NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH;—CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

The term “heteroaliphatic”, as used herein, refers to aliphatic moietiesin which one or more carbon atoms in the main chain have beensubstituted with a heteroatom. Thus, a heteroaliphatic group refers toan aliphatic chain which contains one or more oxygen, sulfur, nitrogen,phosphorus or silicon atoms, e.g., in place of carbon atoms.Heteroaliphatic moieties may be linear or branched, and saturated orunsaturated. In certain embodiments, heteroaliphatic moieties aresubstituted by independent replacement of one or more of the hydrogenatoms thereon with one or more moieties including, but not limited toaliphatic; alicyclic; heteroaliphatic; heterocyclic; aromatic;heteroaromatic; aryl; heteroaryl; alkylaryl; alkylheteroaryl; alkoxy;aryloxy; heteroalkoxy; heteroaryloxy; alkylthio; arylthio;heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH; —NO₂; —CN; —CF₃;—CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂; —CH₂SO₂CH₃; —C(O)R_(x);—CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x); —OCO₂R_(x); —OCON(R_(x))₂;—N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x) wherein each occurrence ofR_(x) independently includes, but is not limited to, aliphatic,alicyclic, heteroaliphatic, heterocyclic, aromatic, heteroaromatic,aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl orheteroalkylheteroaryl, wherein any of the aliphatic, alicyclic,heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl or heteroarylsubstituents described above and herein may be substituted orunsubstituted. Additional examples of generally applicable substituentsare illustrated by the specific embodiments shown in the Examples thatare described herein.

The term “heterocycloalkyl”, “heterocycle” or “heterocyclic”, as usedherein, refers to compounds which combine the properties ofheteroaliphatic and cyclic compounds and include, but are not limitedto, saturated and unsaturated mono- or polycyclic cyclic ring systemshaving 5-16 atoms wherein at least one ring atom is a heteroatomselected from O, S and N (wherein the nitrogen and sulfur heteroatomsmay be optionally be oxidized), wherein the ring systems are optionallysubstituted with one or more functional groups, as defined herein. Incertain embodiments, the term “heterocycloalkyl”, “heterocycle” or“heterocyclic” refers to a non-aromatic 5-, 6- or 7-membered ring or apolycyclic group wherein at least one ring atom is a heteroatom selectedfrom O, S and N (wherein the nitrogen and sulfur heteroatoms may beoptionally be oxidized), including, but not limited to, a bi- ortri-cyclic group, comprising fused six-membered rings having between oneand three heteroatoms independently selected from oxygen, sulfur andnitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds, each6-membered ring has 0 to 2 double bonds and each 7-membered ring has 0to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms may beoptionally be oxidized, (iii) the nitrogen heteroatom may optionally bequaternized, and (iv) any of the above heterocyclic rings may be fusedto an aryl or heteroaryl ring. Representative heterocycles include, butare not limited to, heterocycles such as furanyl, thiofuranyl, pyranyl,pyrrolyl, thienyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolyl,oxazolidinyl, isooxazolyl, isoxazolidinyl, dioxazolyl, thiadiazolyl,oxadiazolyl, tetrazolyl, triazolyl, thiatriazolyl, oxatriazolyl,thiadiazolyl, oxadiazolyl, morpholinyl, thiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, dithiazolyl, dithiazolidinyl,tetrahydrofuryl, and benzofused derivatives thereof. In certainembodiments, a “substituted heterocycle, or heterocycloalkyl orheterocyclic” group is utilized and as used herein, refers to aheterocycle, or heterocycloalkyl or heterocyclic group, as definedabove, substituted by the independent replacement of one, two or threeof the hydrogen atoms thereon with but are not limited to aliphatic;alicyclic; heteroaliphatic; heterocyclic; aromatic; heteroaromatic;aryl; heteroaryl; alkylaryl; heteroalkylaryl; alkylheteroaryl;heteroalkylheteroaryl; alkoxy; aryloxy; heteroalkoxy; heteroaryloxy;alkylthio; arylthio; heteroalkylthio; heteroarylthio; F; Cl; Br; I; —OH;—NO₂; —CN; —CF₃; —CH₂CF₃; —CHCl₂; —CH₂OH; —CH₂CH₂OH; —CH₂NH₂;—CH₂SO₂CH₃; —C(O)R_(x); —CO₂(R_(x)); —CON(R_(x))₂; —OC(O)R_(x);—OCO₂R_(x); —OCON(R_(x))₂; —N(R_(x))₂; —S(O)₂R_(x); —NR_(x)(CO)R_(x)wherein each occurrence of R_(x) independently includes, but is notlimited to, aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic, heteroaromatic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl, wherein any of the aliphatic,alicyclic, heteroaliphatic, heterocyclic, alkylaryl, or alkylheteroarylsubstituents described above and herein may be substituted orunsubstituted, branched or unbranched, saturated or unsaturated, andwherein any of the aromatic, heteroaromatic, aryl or heteroarylsubstitutents described above and herein may be substituted orunsubstituted. Additional examples or generally applicable substituentsare illustrated by the specific embodiments shown in the Examples, whichare described herein.

Additionally, it will be appreciated that any of the alicyclic orheterocyclic moieties described above and herein may comprise an aryl orheteroaryl moiety fused thereto. Additional examples of generallyapplicable substituents are illustrated by the specific embodimentsshown in the Examples that are described herein.

The terms “halo” and “halogen” as used herein refer to an atom selectedfrom fluorine, chlorine, bromine and iodine.

The term “haloalkyl” denotes an alkyl group, as defined above, havingone, two, or three halogen atoms attached thereto and is exemplified bysuch groups as chloromethyl, bromoethyl, trifluoromethyl, and the like.

The term “amino”, as used herein, refers to a primary (—NH₂), secondary(—NHR_(x)), tertiary (—NR_(x)R_(y)) or quaternary (—N⁺R_(x)R_(y)R_(z))amine, where R_(x), R_(y) and R_(z) are independently an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromaticmoiety, as defined herein. Examples of amino groups include, but are notlimited to, methylamino, dimethylamino, ethylamino, diethylamino,diethylaminocarbonyl, methylethylamino, iso-propylamino, piperidino,trimethylamino, and propylamino.

The term “acyl”, as used herein, refers to a group having the generalformula —C(═O)R, where R is an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aromatic or heteroaromatic moiety, as defined herein.

The term “sulfonamido”, as used herein, refers to a group of the generalformula —SO₂NR_(x)R_(y), where R_(x) and R_(y) are independentlyhydrogen, or an aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic, heteroaromatic or acyl moiety, as defined herein.

The term “benzamido”, as used herein, refers to a group of the generalformula PhNR_(x)—, where R_(x) is hydrogen, or an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aromatic, heteroaromatic or acyl moiety,as defined herein.

The term “C₁₋₆alkylidene”, as used herein, refers to a substituted orunsubstituted, linear or branched saturated divalent radical consistingsolely of carbon and hydrogen atoms, having from one to six carbonatoms, having a free valence “-” at both ends of the radical.

The term “C₂₋₆alkenylidene”, as used herein, refers to a substituted orunsubstituted, linear or branched unsaturated divalent radicalconsisting solely of carbon and hydrogen atoms, having from two to sixcarbon atoms, having a free valence “-” at both ends of the radical, andwherein the unsaturation is present only as double bonds and wherein adouble bond can exist between the first carbon of the chain and the restof the molecule.

As used herein, the terms “aliphatic”, “heteroaliphatic”, “alkyl”,“alkenyl”, “alkynyl”, “heteroalkyl”, “heteroalkenyl”, “heteroalkynyl”,and the like encompass substituted and unsubstituted, saturated andunsaturated, and linear and branched groups. Similarly, the terms“alicyclic”, “heterocyclic”, “heterocycloalkyl”, “heterocycle” and thelike encompass substituted and unsubstituted, and saturated andunsaturated groups. Additionally, the terms “cycloalkyl”,“cycloalkenyl”, “cycloalkynyl”, “heterocycloalkyl”,“heterocycloalkenyl”, “heterocycloalkynyl”, “aromatic”,“heteroaromatic”, “aryl”, “heteroaryl” and the like encompass bothsubstituted and unsubstituted groups.

By the term “protecting group”, has used herein, it is meant that aparticular functional moiety, e.g., O, S, or N, is temporarily blockedso that a reaction can be carried out selectively at another reactivesite in a multifunctional compound. In preferred embodiments, aprotecting group reacts selectively in good yield to give a protectedsubstrate that is stable to the projected reactions; the protectinggroup must be selectively removed in good yield by readily available,preferably nontoxic reagents that do not attack the other functionalgroups; the protecting group forms an easily separable derivative (morepreferably without the generation of new stereogenic centers); and theprotecting group has a minimum of additional functionality to avoidfurther sites of reaction. As detailed herein, oxygen, sulfur, nitrogenand carbon protecting groups may be utilized. For example, in certainembodiments, as detailed herein, certain exemplary oxygen protectinggroups are utilized. These oxygen protecting groups include, but are notlimited to methyl ethers, substituted methyl ethers (e.g., MOM(methoxymethyl ether), MTM (methylthiomethyl ether), BOM(benzyloxymethyl ether), PMBM or MPM (p-methoxybenzyloxymethyl ether),to name a few), substituted ethyl ethers, substituted benzyl ethers,silyl ethers (e.g., TMS (trimethylsilyl ether), TES(triethylsilylether), TIPS (triisopropylsilyl ether), TBDMS(T-butyldimethylsilyl ether), tribenzyl silyl ether, TBDPS(T-butyldiphenyl silyl ether), to name a few), esters (e.g., formate,acetate, benzoate (Bz), trifluoroacetate, dichloroacetate, to name afew), carbonates, cyclic acetals and ketals. In certain other exemplaryembodiments, nitrogen protecting groups are utilized. These nitrogenprotecting groups include, but are not limited to, carbamates (includingmethyl, ethyl and substituted ethyl carbamates (e.g., Troc), to name afew) amides, cyclic imide derivatives, N-Alkyl and N-Aryl amines, iminederivatives, and enamine derivatives, to name a few. Certain otherexemplary protecting groups are detailed herein, however, it will beappreciated that the present invention is not intended to be limited tothese protecting groups; rather, a variety of additional equivalentprotecting groups can be readily identified using the above criteria andutilized in the present invention. Additionally, a variety of protectinggroups are described in “Protective Groups in Organic Synthesis” ThirdEd. Greene, T. W. and Wuts, P. G., Eds., John Wiley & Sons, New York:1999, the entire contents of which are hereby incorporated by reference.

The term “natural amino acid” as used herein refers to any one of thecommon, naturally occurring L-amino acids found in naturally occurringproteins: glycine (Gly), alanine (Ala), valine (Val), leucine (Leu),isoleucine (Ile), lysine (Lys), arginine (Arg), histidine (His), proline(Pro), serine (Ser), threonine (Thr), phenylalanine (Phe), tyrosine(Tyr), tryptophan (Trp), aspartic acid (Asp), glutamic acid (Glu),asparagine (Asn), glutamine (Gln), cysteine (Cys) and methionine (Met).

The term “unnatural amino acid” as used herein refers to all amino acidswhich are not natural amino acids. This includes, for example, α-, β-,D-, L-amino acid residues, and compounds of the general formula

wherein the side chain R is other than the amino acid side chainsoccurring in nature.

More generally, the term “amino acid”, as used herein, encompassesnatural amino acids and unnatural amino acids.

The term “bioisosteres”, as used herein, generally refers to two or morecompounds or moieties that possess similar molecular shapes and/orvolumes. In certain embodiments, bioisosteres have approximately thesame distribution of electrons. In certain other embodiments,bioisosteres exhibit similar biological properties. In preferredembodiments, bioisosteres possess similar molecular shapes and volumes;have approximately the same distribution of electrons; and exhibitsimilar biological properties.

As used herein, the term “isolated”, when applied to the compounds ofthe present invention, refers to such compounds that are (i) separatedfrom at least some components with which they are associated in natureor when they are made and/or (ii) produced, prepared or manufactured bythe hand of man.

The term, “pharmaceutically acceptable derivative”, as used herein,denotes any pharmaceutically acceptable salt, ester, or salt of suchester, of such compound, or any other adduct or derivative which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound as otherwise described herein, or a metabolite orresidue thereof. Pharmaceutically acceptable derivatives thus includeamong others pro-drugs. A pro-drug is a derivative of a compound,usually with significantly reduced pharmacological activity, whichcontains an additional moiety, which is susceptible to removal in vivoyielding the parent molecule as the pharmacologically active species. Anexample of a pro-drug is an ester, which is cleaved in vivo to yield acompound of interest. Pro-drugs of a variety of compounds, and materialsand methods for derivatizing the parent compounds to create thepro-drugs, are known and may be adapted to the present invention.Certain exemplary pharmaceutical compositions and pharmaceuticallyacceptable derivatives will be discussed in more detail herein below.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts of amines, carboxylic acids, and other types ofcompounds, are well known in the art. For example, S. M. Berge, et al.describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein byreference. The salts can be prepared in situ during the final isolationand purification of the compounds of the invention, or separately byreacting a free base or free acid function with a suitable reagent, asdescribed generally below. For example, a free base function can bereacted with a suitable acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may, include metal salts such as alkali metal salts, e.g.sodium or potassium salts; and alkaline earth metal salts, e.g. calciumor magnesium salts. Examples of pharmaceutically acceptable, nontoxicacid addition salts are salts of an amino group formed with inorganicacids such as hydrochloric acid, hydrobromic acid, phosphoric acid,sulfuric acid and perchloric acid or with organic acids such as aceticacid, oxalic acid, maleic acid, tartaric acid, citric acid, succinicacid or malonic acid or by using other methods used in the art such asion exchange. Other pharmaceutically acceptable salts include adipate,alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate,borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hernisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Representative alkali or alkaline earth metal salts includesodium, lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, loweralkyl sulfonate and aryl sulfonate.

As used herein, the term “pharmaceutically acceptable ester” refers toesters that hydrolyze in vivo and include those that break down readilyin the human body to leave the parent compound or a salt thereof.Suitable ester groups include, for example, those derived frompharmaceutically acceptable aliphatic carboxylic acids, particularlyalkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which eachalkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.Examples of particular esters include formates, acetates, propionates,butyrates, acrylates and ethylsuccinates.

As used herein, the term “pharmaceutically acceptable prodrugs” refersto those prodrugs of the compounds of the present invention which are,within the scope of sound medical judgment, suitable for use in contactwith the issues of humans and lower animals with undue toxicity,irritation, allergic response, and the like, commensurate with areasonable benefit/risk ratio, and effective for their intended use, aswell as the zwitterionic forms, where possible, of the compounds of theinvention. The term “prodrug” refers to compounds that are rapidlytransformed in vivo to yield the parent compound of the above formula,for example by hydrolysis in blood. A thorough discussion is provided inT. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, VoL. 14of the A.C.S. Symposium Series, and in Edward B. Roche, ed.,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, both of which are incorporatedherein by reference.

The term “LFA-1 mediated disorders”, as used herein refers generally topathological states caused by cell adherence interactions involving theLFA-1 receptor on lymphocytes. Examples of such disorders include, butare not limited to T-cell inflammatory responses such as inflammatoryskin diseases including psoriasis; responses associated withinflammatory bowel disease (such as Crohn's disease and ulcerativecolitis); adult respiratory distress syndrome, dermatitis, meningitis,encephalitis, uveitic, allergic conditions such as eczema and asthma andother conditions involving infiltration of T-cells and chronicinflammatory responses, skin hypersensitivity reactions (includingpoison ivy and poison oak), atherosclerosis, leukocyte adhesiondeficiency, autoimmune diseases such as rheumatoid arthritis, systemiclupus erythematosus (SLE), diabetes mellitus, multiple sclerosis,Reynaud's syndrome, autoimmune thyroiditis, experimental autoimmuneencephalomyelitis, Sjorgen's syndrome, type 1 diabetes, juvenile onsetdiabetes, and immune responses associated with delayed hypersensitivitymediated by cytokines and T-lymphocytes typically found in tuberculosis,sarcoidosis, polymyositis, granulomatosis, and vasculitis, perniciousanemia, diseases involving leukocyte diapedesis, CNS inflammatorydisorder, multiple organ injury syndrome secondary to septicaemia ortrauma, autoimmune haemolytic anemia, myethamia gravis, antigen-antibodycomplex mediated diseases, and all types of transplantations, includinggraft vs. host or host vs. graft disease.

The term “LFA-1 antagonist”, as used herein, generally refers toinventive compounds, as described herein, that act as a competitiveinhibitors of the CD11a and/or CD18 interaction with ICAM-1, ICAM-2 orICAM-3.

The term “treating”, as used herein generally means that the compoundsof the invention can be used in humans or animals with at least atentative diagnosis of disease. The compounds of the invention willdelay or slow the progression of the disease thereby extending theindividual's life span.

The term “preventing” as used herein generally means that the compoundsof the present invention are useful when administered to a patient whohas not been diagnosed as possibly having the disease at the time ofadministration, but who would normally be expected to develop thedisease or be at increased risk for the disease. In certain embodiments,compounds of the invention slow the development of disease symptoms,delay the onset of disease, or prevent the individual from developingthe disease at all.

As used herein the term “biological sample” includes, withoutlimitation, cell cultures or extracts thereof; biopsied materialobtained from an animal (e.g., mammal) or extracts thereof; and blood,saliva, urine, feces, semen, tears, or other body fluids or extractsthereof. For example, the term “biological sample” refers to any solidor fluid sample obtained from, excreted by or secreted by any livingorganism, including single-celled micro-organisms (such as bacteria andyeasts) and multicellular organisms (such as plants and animals, forinstance a vertebrate or a mammal, and in particular a healthy orapparently healthy human subject or a human patient affected by acondition or disease to be diagnosed or investigated). The biologicalsample can be in any form, including a solid material such as a tissue,cells, a cell pellet, a cell extract, cell homogenates, or cellfractions; or a biopsy, or a biological fluid. The biological fluid maybe obtained from any site (e.g. blood, saliva (or a mouth washcontaining buccal cells), tears, plasma, serum, urine, bile,cerebrospinal fluid, amniotic fluid, peritoneal fluid, and pleuralfluid, or cells therefrom, aqueous or vitreous humor, or any bodilysecretion), a transudate, an exudate (e.g. fluid obtained from anabscess or any other site of infection or inflammation), or fluidobtained from a joint (e.g. a normal joint or a joint affected bydisease such as rheumatoid arthritis, osteoarthritis, gout or septicarthritis). The biological sample can be obtained from any organ ortissue (including a biopsy or autopsy specimen) or may comprise cells(whether primary cells or cultured cells) or medium conditioned by anycell, tissue or organ. Biological samples may also include sections oftissues such as frozen sections taken for histological purposes.Biological samples also include mixtures of biological moleculesincluding proteins, lipids, carbohydrates and nucleic acids generated bypartial or complete fractionation of cell or tissue homogenates.Although the sample is preferably taken from a human subject, biologicalsamples may be from any animal, plant, bacteria, virus, yeast, etc. Theterm animal, as used herein, refers to humans as well as non-humananimals, at any stage of development, including, for example, mammals,birds, reptiles, amphibians, fish, worms and single cells. Cell culturesand live tissue samples are considered to be pluralities of animals. Incertain exemplary embodiments, the non-human animal is a mammal (e.g., arodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep,cattle, a primate, or a pig). An animal may be a transgenic animal or ahuman clone. If desired, the biological sample may be subjected topreliminary processing, including preliminary separation techniques.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

The present invention provides compounds that modulate interactionsbetween intracellular adhesion molecules (e.g., ICAM-1, -2 and -3) andthe leukocyte integrin family of receptors. In certain embodiments, theinventive compounds are antagonists and are useful for the treatment ofCD11/CD18 mediated disorders. In certain embodiments of specialinterest, the inventive compounds are useful for the treatment of Mac-1and LFA-1 mediated disorders. In still other embodiments, the compoundsare useful for the treatment of LFA-1 mediated disorders, for example,inflammatory disorders and autoimmune disorders to name a few.

1) General Description of Compounds of the Invention

The compounds of the invention include compounds of the general formula(I) as further defined below:

and pharmaceutically acceptable derivatives thereof;

wherein R¹ and R² are each independently hydrogen, an amino acid sidechain, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromaticor heteroaromatic moiety, or wherein R¹ and R² taken together are analicyclic or heterocyclic moiety, or together are

wherein R^(1A) is hydrogen, an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aromatic or heteroaromatic moiety;

R³ is —C(═O)OR^(3A), —C(═O)H, —CH₂OR^(3A), —CH₂O—C(═O)-alkyl,—C(═O)NH(R^(3A)) or —CH₂X⁰; wherein each occurrence of R^(3A) isindependently hydrogen, a protecting group, an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety, orR^(3A), taken together with R¹ or R², forms a heterocyclic moiety;wherein X⁰ is a halogen selected from F, Cl, Br or I;

R⁴, for each occurrence, is independently hydrogen, halogen, —CN, —NO₂,an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic orheteroaromatic moiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—,—CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2), —OC(═O)—, —NR^(G2)C(═O)— or—SO₂NR^(G2)—, and R^(G1) and R^(G2) are independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic orheteroaromatic moiety;

n is an integer from 0-3;

AR¹ is an aromatic, heteroaromatic, alicyclic or heterocyclic moiety;

A, B, D and E are connected by either a single or double bond, asvalency permits; wherein each occurrence of A, B, D and E isindependently C═O, CR^(i)R^(ii), NR^(i), CR^(i), N, O, S, S(═O) or SO₂;wherein each occurrence of R^(i) is independently hydrogen, halogen,—CN, —NO₂, an aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic or heteroaromatic moiety, or is -GR^(G1) wherein G is —O—, —S—,—NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2), —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic,aromatic or heteroaromatic moiety, or any two adjacent occurrences ofR^(i), taken together, represent an alicyclic, heterocyclic, aromatic orheteroaromatic moiety;

p is an integer from 0-4; and

L is absent or is V-W-X-Y-Z, wherein each occurrence of V, W, X, Y and Zis independently absent, C═O, NR^(L1), —O—, —C(R^(L1))═, ═C(R^(L1))—,—C(R^(L1))(R^(L2)), C(═N—O—R^(L1)), C(═N—R^(L1)), —N═, S(O)₀₋₂; asubstituted or unsubstituted C₁₋₆alkylidene or C₂₋₆alkenylidene chainwherein up to two non-adjacent methylene units are independentlyoptionally replaced by —C(═O)—, —CO₂—, —C(═O)C(═O)—, —C(═O)NR^(L3)—,—OC(═O)—, —OC(═O)NR^(L3)—, —NR^(L3)NR^(L4)—, —NR^(L3)NR^(L4)C(═O)—,—NR^(L3)C(═O)—, —NR^(L3)CO₂—, —NR^(L3)C(═O)NR^(L4)—, —S(═O)—, —SO₂—,—NR^(L3)SO₂—, —SO₂NR^(L3)—, —NR^(L3)SO₂NR^(L4)—, —O—, —S—, or —NR^(L3)—;wherein each occurrence of R^(L3) and R^(L4) is independently hydrogen,alkyl, heteroalkyl, aromatic, heteroaromatic or acyl; or an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aromatic or heteroaromaticmoiety; and each occurrence of R^(L1) and R^(L2) is independentlyhydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio,protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl,formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato,alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or analiphatic, alicyclic, heteroaliphatic, heterocyclic, aromatic orheteroaromatic moiety, or wherein one or more occurrences of R^(L1) andR^(L2), taken together, or taken together with one of V, W, X, Y or Zform an alicyclic or heterocyclic moiety or form an aromatic orheteroaromatic moiety.

In another aspect, the invention provides compounds of formula (II):

wherein AR has one of the following structures:

and pharmaceutically acceptable derivatives thereof;

wherein R¹, R², R³, R⁴, A, B, D, E, n, p are as defined generally aboveand in classes and subclasses herein; and

Y¹, Y² and Y³ are each independently CR⁴ or N;

with the proviso that, when AR has the structure:

wherein Y¹ is CH or N and p is 0-2,

then R⁴ is not carbocycle, aryl, heteroaryl or heterocyle, and A, B, Dand E do not comprise a carbocyclic, aryl, heteroaryl or heterocyclicmoiety.

In certain embodiments, for compounds of formula (II), AR represents amoiety having one of the following structures:

wherein each occurrence of n is an integer from 0-6; each occurrence ofR⁴ is independently hydrogen, halogen, CN, isocyanate, NO₂,—P(═O)(YR^(P5))₂, an alkyl, cycloalkyl, heteroalkyl, heterocyclicmoiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—, —CO—, —SO—,—SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)— or—SO₂NR^(G2)—, and R^(G1) and R^(G2) are independently hydrogen, analkyl, cycloalkyl, heteroalkyl, heterocyclic moiety; each occurrence ofY is independently a bond or O; each occurrence of R^(P5) isindependently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is OR^(P5) may also be hydrogen; and each occurrence of R^(4A) isindependently hydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclicmoiety or a nitrogen protecting group; wherein any two adjacentoccurrences of R⁴ and R^(4A), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety. In certain exemplaryembodiments, AR has the structure:

In yet other exemplary embodiments, AR has the structure:

wherein each occurrence of X₀ is independently a halogen selected fromF, Cl, Br and I. In certain embodiments, each occurrence of X⁰ is Cl.

A number of important subclasses of each of the foregoing classesdeserve separate mention; these subclasses include subclasses of theforegoing classes in which:

i) R¹ and R² are each independently hydrogen, an amino acid side chain,—(CH₂)_(m)OH, —(CH₂)_(m)aryl, —(CH₂)_(m)heteroaryl, wherein m is 0-6,—CH(R^(1A))(OR^(1B)), —CH(R^(1A))(NHR^(1B)), U-T-Q, or an alkyl,cycloalkyl, heteroalkyl or heterocyclic moiety optionally substitutedwith U-T-Q, wherein U is absent, —O—, —S(O)₀₋₂—, —SO₂N(R^(1A)),—N(R^(1A))—, —N(R^(1A))C(═O)—, —N(R^(1A))C(═O)—O—,—N(R^(1A))C(═O)—N(R^(1B))—, —N(R^(1A))—SO₂—, —C(═O)—, —C(═O)—O—,—O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl,—C(═O)—N(R^(1A))—, —O—C(═O)—N(R^(1A))—, —C(═N—R^(1E))—,—C(═N—R^(1E))—O—, —C(═N—R^(1E))—N(R^(1A))—, —O—C(═N—R^(1E))—N(R^(1A))—,—N(R^(1A))C(═N—^(1E))—, —N(R^(1A))C(═N—R^(1E))—O—,N(R^(1A))C(═N—R^(1E))—N(R^(1B))—, —P(═O)(OR^(1A))—O—, or—P(═O)(R^(1A))—O—; wherein T is absent, an alkyl, cycloalkyl,heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl or heteroalkylheteroaryl moiety, and wherein Q ishydrogen, halogen, cyano, isocyanate, —OR^(1B), —SR^(1B); —N(R^(1B))₂,—NHC(═O)OR^(1B), —NHC(═O)N(R^(1B))₂, —NHC(═O)R^(1B), —NHSO₂R^(1B),—NHSO₂N(R^(1B))₂, —NHSO₂NHC(═O)OR^(1B), —NHC(═O)NHSO₂R^(1B),—C(═O)NHC(═O)OR^(1B), —C(═O)NHC(═O)R^(1B), —C(═O)NHC(═O)N(R^(1B))₂,—C(═O)NHSO₂R^(1B), —C(═O)NHSO₂N(R^(1B))₂; —C(═S)N(R^(1B))₂, —SO₂R^(1B),—SO₂R^(1B), —SO₂—N(R^(1B))₂, —SO₂—NHC(═O)OR^(1B),—SO₂—NHC(═O)—N(R^(1B))₂, —SO₂—NHC(═O)R^(1B), —O—C(═O)N(R^(1B))₂,—O—C(═O)R^(1B), —O—C(═O)NHC(═O)R^(1B), —O—C(═O)NH—SO₂R^(1B),—O—SO₂R^(1B), or an alkyl, cycloalkyl, heteroalkyl, heterocyclic, arylor heteroaryl moiety, or wherein R¹ and R² taken together are acycloalkyl or heterocyclic moiety, or together are

wherein each occurrence of R^(1A) and R^(1B) is independently hydrogen,an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroarylmoiety, —COR^(1C), or —CONR^(1C)R^(1D); wherein each occurrence ofR^(1C) and R^(1D) is independently hydrogen, hydroxyl, or an alkyl,cycloalkyl, heteroalkyl, heterocyclic, aryl or heteroaryl moiety; andR^(1E) is hydrogen, an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety,—CN, —OR^(1C), —NR^(1C)R^(1D) or —SO₂R^(1C);

ii) R³ is carboxyl, protected carboxyl or a prodrug thereof, wherein R³is C(═O)R^(3A), wherein R^(3A) is hydroxy, alkoxy, cycloalkoxy,aralkoxy, arcycloalkoxy, aryloxy, alkylcarbonyloxyalkyloxy,alkoxycarbonyloxyalkyloxy, alkoxycarbonylalkyloxy,cycloalkylcarbonyloxyalkyloxy, cycloalkoxycarbonyloxyalkyloxy,cycloalkoxycarbonylalkyloxy, arylcarbonyloxyalkyloxy,aryloxycarbonyloxyalkyloxy, arylcarbonyloxyalkyloxy,alkoxyalkylcarbonyloxyalkyloxy, or one or the structures:

iii) R³ is —C(═O)OR^(3A), —C(═O)H, —CH₂OR^(3A), —CH₂O—C(═O)-alkyl,—C(═O)NH(R^(3A)), or —CH₂X⁰; wherein each occurrence of R^(3A) isindependently hydrogen, a protecting group, an alkyl, cycloalkyl,heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety, or R^(3A), taken together with R¹ or R², forms aheterocyclic moiety; wherein X⁰ is a halogen selected from F, Cl, Br orI;

iv) R³ is —C(═O)OR^(3A); wherein R^(3A) is hydrogen, a protecting group,an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or R^(3A), taken together with R¹or R², forms a heterocyclic moiety;

v) R³ is —C(═O)OR^(3A); wherein R^(3A) is C₁₋₅alkyl;

vi) R³ is —C(═O)OR^(3A); wherein R^(3A) is C₁₋₃alkyl;

vii) R³ is —C(═O)OR^(3A); wherein R^(3A) is ethyl;

viii) R³ is —C(═O)OR^(3A); wherein R^(3A) is benzyl;

ix) R³ is CO₂H;

x) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ is a moiety having thefollowing structure:

wherein Ar₂ is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety;and R^(S) is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or is-G⁰R^(G1) wherein G⁰ is —O—, —S— or —NR^(G2)—, and R^(G1) and R^(G2) areindependently hydrogen, an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aromatic or heteroaromatic moiety;

xi) Compounds of subset x) above wherein—C(═O)NHCH(CO₂R^(3A))CH(R^(S))Ar₂ has the following stereochemistry:

xii) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ is a moiety having thefollowing structure:

wherein R^(1A) is Ar₂, —OR^(1B), —SR^(1B) or —NR^(1B)R^(1C); or an alkylor heteroalkyl moiety; and Ar₂ is a cycloalkyl, heterocyclic, aryl orheteroaryl moiety; wherein R^(1B) and R^(1C) are independently hydrogen,alkyl, heteroalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, orR^(1B) and R^(1C), taken together with the nitrogen atom to which theyare attached, form a heterocylic or heteroaryl moiety;

xiii) Compounds of subset xii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂NHC(═O)R^(1A) has the following stereochemistry:

xiv) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ is a moiety having thefollowing structure:

wherein Ar₂ is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety;and R^(2A) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, —C(═O)R^(2B) or—SO₂R^(2B), wherein R^(2B) is alkyl, cycloalkyl, heteroalkyl,heterocyclyl, aryl or heteroaryl; or R^(2A), taken together with asubstituent on Ar₂, forms a substituted or unsubstituted heterocyclic orheteroaryl moiety;

xv) Compounds of subset xiv) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))Ar₂ has the following stereochemistry:

xvi) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ is a moiety having thefollowing structure:

wherein R^(2A) is hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl,—C(═O)R^(2B) or —SO₂R^(2B), wherein R^(2B) is alkyl, cycloalkyl,heteroalkyl, heterocyclyl, aryl or heteroaryl; or R^(2A), taken togetherwith R^(2C) or R^(2D), forms a substituted or unsubstituted heterocyclicor heteroaryl moiety; R^(2C) is hydrogen, CN, —C═NMe, ═NO₂, ═NC(═O)NH₂,═NS(O)₂R, ═NS(O)₂NRR′, —SO₂R^(2G), or an aliphatic, alicyclic,heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety; wherein R and R′ are each independently hydrogenor methyl, and R^(2G) is lower alkyl; and R^(2D) is Ar₂, hydrogen,halogen, CN, NO₂, an aliphatic, heteroaliphatic, alkylaryl oralkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—,—CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)— or—SO₂NR^(G2)—, and R^(G1) and R^(G2) are independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety;

xvii) Compounds of subset xvi) above wherein the—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstereochemistry:

xviii) Compounds of subset xvii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstructure:

wherein R^(2E) and R^(2F) are each independently hydrogen, or analiphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety, or R^(2E) and R^(2F),taken together, form a substituted or unsubstituted heterocyclic orheteroaryl moiety;

xix) Compounds of subset xvii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(NR^(2C))R^(2D) has the followingstructure:

wherein R^(2C) is hydrogen, CN, —C═NMe, ═NO₂, ═NC(═O)NH₂, ═NS(O)₂R, or═NS(O)₂NRR′; wherein R and R′ are each independently hydrogen or methyl;

xx) Compounds of subset xvii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstructure:

wherein R^(2C) is hydrogen, CN, —C═NMe, ═NO₂, ═NC(═O)NH₂, ═NS(O)₂R, or═NS(O)₂NRR′; wherein R and R′ are each independently hydrogen or methyl;

xxi) Compounds of subset xvii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstructure:

xxii) Compounds of subset xvii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstructure:

xxiii) Compounds of subsets xvii) and xviii) above wherein—C(═O)NHCH(CO₂R^(3A))CH₂N(R^(2A))C(═NR^(2C))R^(2D) has the followingstructure:

or bioisosteres thereof;

wherein R^(2A), R^(2D), R^(2E) and R^(2F) are as defined in xvi) andxviii) above;

xxiv) Compounds of subset xxiii) above wherein the bioiosteres have oneof the following structures:

wherein R^(2C) is lower alkyl;

xxv) Compounds of subset xxiii) above wherein R^(2D) is, or R^(2E) andR^(2F) together with the nitrogen atom to which they are attached form,a moiety having one of the structures:

wherein s is an integer between 0 and 6; each occurrence of R^(P1) isindependently hydrogen, halogen, CN, isocyanate, NO₂, —P(═O)(YR^(P5))₂,an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—,—S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y isindependently a bond or O; each occurrence of R^(P5) is independentlyalkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R^(P5) may alsobe hydrogen; and each occurrence of R^(P2) is independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroarylmoiety or a nitrogen protecting group; wherein any two adjacentoccurrences of R^(P1) and R^(P2), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety;

xxvi) Compounds of subset xxv) above wherein R^(2D) is, or R^(2E) andR^(2F) together with the nitrogen atom to which they are attached form,a moiety having one of the structures:

wherein each occurrence of R^(P1) is independently hydrogen, halogen,methyl, —OCH₃, —OH, —NH₂, —NHCH₃, or —N(CH₃)₂;

xxvii) Compounds of subset xxvi) above wherein R^(2D) is, or R^(2E) andR^(2F) together with the nitrogen atom to which they are attached form,a moiety having one of the structures:

xxviii) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ is a moiety having thefollowing structure:

wherein Ar₂ is a cycloalkyl, heterocyclic, aryl or heteroaryl moiety;

xxix) Compounds of subsets x)-xii), xiv)-xv) and xxviii); and compoundsof subset xvi) wherein R^(2D) is Ar₂; wherein Ar₂ is one of thefollowing structures:

wherein each occurrence of s is an integer from 0-6; w is an integerfrom 1-6; X₁ is CHR^(P1) or NR^(P2); X₂ and X₃ are independentlyCHR^(P1), NR^(P2), CHSO₂R^(P3) or NSO₂R^(P3); each occurrence of R^(P1)is independently hydrogen, halogen, CN, isocyanate, NO₂,—P(═O)(YR^(P5))₂, an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aryl, heteroaryl, -(aliphatic)aryl or-(aliphatic)heteroaryl moiety, or is -GR^(G1) wherein G is —O—, —S—,—NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, -(aliphatic)aryl or -(aliphatic)heteroaryl moiety; eachoccurrence of Y is independently a bond or O; each occurrence of R^(P5)is independently alkyl, heteroalkyl, aryl or heteroaryl, or when Y is OR^(P5) may also be hydrogen; and each occurrence of R^(P2) isindependently hydrogen, an aliphatic, alicyclic, heteroaliphatic,heterocyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl,heteroalkylaryl, or heteroalkylheteroaryl moiety or a nitrogenprotecting group; wherein any two adjacent occurrences of R^(P1) andR^(P2), taken together, may form a cycloalkyl, heterocyclic, aryl orheteroaryl moiety; and each occurrence of R^(P3) is independently alkyl,aryl, heteroaryl or —N(R^(P2))₂.

xxx) Compounds of subset xxix) above wherein Ar₂ is one of the followingstructures:

wherein s, X¹, X² and X³ are as defined in xx) above; X⁵ is O, S orNR^(P2); each occurrence of R^(P1) is independently hydrogen, halogen,CN, isocyanate, NO₂, —P(═O)(YR^(P5))₂, an alkyl, cycloalkyl,heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—,—CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)— or—SO₂NR^(G2)—, and R^(G1) and R^(G2) are independently hydrogen, analkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety; each occurrence of Y isindependently a bond or O; each occurrence of R^(P5) is independentlyalkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R^(P5) may alsobe hydrogen; each occurrence of R^(P2) is independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroarylmoiety or a nitrogen protecting group; wherein any two adjacentoccurrences of R^(P1) and R^(P2), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety; and each occurrence of R^(P3)is independently alkyl, aryl, heteroaryl or —N(R^(P2))₂;

xxxi) Compounds of subset xxx) above wherein each occurrence of R^(P1)is independently hydrogen, halogen, —P(═O)(YR^(P5))₂, lower alkyl orheteroalkyl moiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)— or—SO₂—, and R^(G1) and R^(G2) are independently hydrogen, lower alkyl oraryl; each occurrence of Y is independently a bond or O; each occurrenceof R^(P5) is independently lower alkyl, or when Y is O R^(P5) may alsobe hydrogen; and each occurrence of R^(P2) is independently hydrogen,lower alkyl or a nitrogen protecting group; wherein any two adjacentoccurrences of R^(P1) and R^(P2), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety;

xxxii) Compounds of subset xxx) above wherein Ar₂ has one of thefollowing structures:

wherein X₁ is N or CR^(P1); s is an integer from 0-6; each occurrence ofR^(P1) is independently hydrogen, halogen, CN, NO₂, an alkyl,cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—,—CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —R^(G2)C(═O)— or—SO₂NR^(G2)—, and R^(G1) and R^(G2) are independently hydrogen, analkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety; and R^(P3) is independently loweralkyl or aryl;

xxxiii) Compounds of subsets xxix), xxx) and xxxii) wherein s is 0;

xxxiv) Compounds of subsets xxix), xxx) and xxxii) wherein s is 1;

xxxv) Compounds of subsets xxix), xxx) and xxxii) wherein s is 2;

xxxvi) Compounds of subsets x) and xi) above wherein Ar₂ is one of thefollowing structures:

wherein s is an integer from 0-2; each occurrence of R^(P1) isindependently hydrogen, halogen, CN, isocyanate, NO₂, —OR^(G1), —SR^(G1), —NR^(G1)R^(G2)—, an alkyl, cycloalkyl, heteroalkyl,heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;each occurrence of Y is independently a bond or O; each occurrence ofR^(P5) is independently lower alkyl, or when Y is O R^(P5) may also behydrogen; each occurrence of R^(P2) is independently hydrogen, alkyl,cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or anitrogen protecting group; R^(P3) is lower alkyl or —N(R^(P2))₂; andR^(G1) and R^(G2) are independently hydrogen, an alkyl, cycloalkyl,heteroalkyl, heterocyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety;

xxxvii) Compounds of subsets x) and xi) above wherein Ar₂ is one of thefollowing structures:

xxxviii) Compounds of subsets x) and xi) above wherein Ar₂ is one of thefollowing structures:

wherein R^(P3) is lower alkyl; and R^(P2) and R^(G1) are independentlyhydrogen or lower alkyl;

xxxix) Compounds of subsets x) and xi) above wherein Ar₂ is one of thefollowing structures:

wherein R^(P3) is lower alkyl and R^(G1) is hydrogen or lower alkyl;

xl) Compounds of subsets x) and xi) above wherein R^(S) is hydrogen,hydroxyl or lower alkoxy and Ar₂ is one of the following structures:

wherein R^(P3) is lower alkyl; and R^(G1) is hydrogen or lower alkyl;

xli) Compounds of subsets xii) and xiii) wherein R^(1A) is alkyl or—NR^(1B)R^(1C); wherein R^(1B) and R^(1C) are independently hydrogen orlower alkyl;

xlii) Compounds of subsets xii) and xiii) wherein R^(1A) is —NH₂ or amoiety having the structure:

wherein R^(P1) is independently hydrogen, hydroxyl, lower alkyl or lowerheteroalkyl; and each occurrence of R^(P2) is independently hydrogen orlower alkyl;

xliii) Compounds of subsets xii) and xiii) wherein R^(1A) is —NH₂ or amoiety having the structure:

wherein R^(P1) is hydrogen or lower alkyl;

xliv) Compounds of subsets xii) and xiii) wherein R^(1A) is cycloalkyl,aryl, or a moiety having one of the structures:

wherein s is an integer between 0 and 6; each occurrence of R^(P1) isindependently hydrogen, halogen, CN, isocyanate, NO₂, —P(═O)(YR^(P5))₂,an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—,—S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y isindependently a bond or O; each occurrence of R^(P5) is independentlyalkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R^(P5) may alsobe hydrogen; and each occurrence of R^(P2) is independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroarylmoiety or a nitrogen protecting group; wherein any two adjacentoccurrences of R^(P1) and R^(P2), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety;

xlv) Compounds of subset xliv) wherein s is an integer between 0 and 2;each occurrence of R^(P1) is independently lower alkyl or is -GR^(G1)wherein G is —O— or —NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence ofR^(P2) is independently hydrogen, lower alkyl, aryl or heteroaryl;

xlvi) Compounds of subsets xxi) and xxii) wherein R^(1A) is a moietyhaving one of the structures:

wherein s is an integer between 0 and 2; X⁰ is halogen; each occurrenceof R^(P1) is independently hydrogen, hydroxyl, lower alkyl or lowerheteroalkyl; G is —O— or —NR^(G2)—, and R^(G1) and R^(G2) areindependently hydrogen or lower alkyl; and R^(P2) is independentlyhydrogen or lower alkyl;

xlvii) Compounds of subset xlvi) wherein R^(1A) is a moiety having oneof the structures:

wherein G is —O— or —NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen or lower alkyl;

xlix) compounds of subsets xiv)-xv) above wherein —NH(R^(2A))Ar₂ has oneof the following structures:

wherein X₁ is N or CR^(P1); s is an integer from 0-5; and eachoccurrence of R^(P1) is independently hydrogen, halogen, CN, NO₂, analkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—,—S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; and R^(P3) is alkyl,heteroalkyl, aryl or heteroaryl;

l) compounds of subset xlix) above wherein s is 0;

li) compounds of subset xlix) above wherein R^(P1) is hydrogen, halogenor lower alkyl;

lii) compounds of subset li) above wherein R^(P1) is hydrogen, chloro ormethyl;

liii) compounds of subset xlix) above wherein R^(P3) is lower alkyl;

liv) compounds of subset liii) above wherein R^(P3) is methyl;

lv) compounds of subset xlix) above wherein —NH(R^(2A))Ar₂ has thefollowing structure:

wherein R^(P1) is hydrogen, halogen or lower alkyl;

lvi) compounds of subset xlix) above wherein —NH(R^(2A))Ar₂ has thefollowing structure:

lvii) Compounds of subsets xvii) having the following structure:

or bioisosteres thereof;

wherein each occurrence of R^(P1) is independently hydrogen, halogen,methyl, —OCH₃, —OH, —NH₂, —NHCH₃ or —N(CH₃)₂; R^(2A) is hydrogen,C₁₋₆alkyl, C₂₋₆alkenyl, aryl, heteroaryl, —C(═O)R^(2B) or —SO₂R^(2B),wherein R^(2B) is alkyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl orheteroaryl; and q is 1 or 2;

lviii) Compounds of subset lvii) above wherein the bioisosteres have oneof the following structures:

wherein q is 1 or 2; and R^(2C) is lower alkyl;

lix) Compounds of subset xxviii) wherein —C(═O)NHC(═CHAr₂)CO₂R^(3A) hasone of the following structures:

wherein R^(P3) is lower alkyl or aryl; X₁ and X₂ are independently N orCR^(P1); X₃ is O, S or NR^(P2); wherein R^(P1) is hydrogen, halogen, CN,NO₂, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—,—S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; and R^(P2) is hydrogen,an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl, orheteroalkylheteroaryl moiety;

lx) Compounds of subset xxviii) wherein —C(═O)NHC(═CHAr₂)CO₂R^(3A) hasthe following structure:

wherein X₁ is N or CH;

lxi) R³ is —C(═O)OR^(3A), wherein R^(3A) is as defined in any one ofsubsets ii)-ix) above, and —C(═O)NHC(R¹)(R²)R³ has the structure—C(═O)NHC(═C(R^(S))Ar₂)CO₂R^(3A) wherein R^(3A) and R^(S), takentogether, form a substituted or unsubstituted heterocyclic moiety;

lxii) Compounds of subset lxi) wherein —C(═O)NHC(═C(R^(S))Ar₂)CO₂R^(3A)has one of the following structures:

wherein Ar₂ is as defined in classes and subclasses herein; and X₁ is O,S or NH;

lxiii) Compounds of subset lxi) wherein —C(═O)NHC(═C(R^(S))Ar₂)CO₂R^(3A)has one of the following structures:

wherein X₁ is O, S or NH; and X₂ is N or CH;

lxiv) L is absent, —C(═O), —CH₂C(═O)NH—, —CH₂NH—C(═O)—, —O—CH₂—C(═O)—,—CH₂—CH₂—C(═O)—, —CH═CH—C(═O)NH—CH₂—, —CH(OH)—CH₂—O—,—CH(OH)—CH₂—N(CH₃)—, —CH(OH)—CH₂—CH₂—, —CH₂—CH₂—CH(OH)—, —O—CH₂—CH(OH)—,—O—CH₂—CH(OH)—CH₂—, —O—CH₂—CH₂—CH(OH)—, O—CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—,—CH₂—CH(OH)—CH₂—O, —CH₂—CH₂—O—, —CH—(CH₃)—NH—C(═O)—, —CH₂—NH—SO₂—,—NH—SO₂—CH₂—, —CH₂—SO₂—NH—, —SO₂NH—CH₂—, —C(═O)—NH—C(═O)—,—NH—C(═O)—NH—, —NH—C(═O)—NH—CH₂—, —CH₂—NH—C(═O)—NH—,—C(═O)—NH—CH₂—C(═O)—NH, —NH—C(═O)—O—, —O—C(═O)—NH—; or a substituted orunsubstituted C₁₋₆alkylidene or C₂₋₆alkenylidene chain wherein up to twonon-adjacent methylene units are independently optionally replaced by—C(═O)—, —CO₂—, —C(═O)C(═O)—, —C(═O)NR^(L3)—, —OC(═O)—, —OC(═O)NR^(L3)—,—NR^(L3)NR^(L4)—, —NR^(L3)NR^(L4)C(═O)—, —NR^(L3)C(═O)—, —NR^(L3)CO₂—,—NR^(L3)C(═O)NR^(L4)—, —S(═O)—, —SO₂—, —NR^(L3)SO₂—, SO₂NR^(L3)—,—NR^(L3)SO₂NR^(L4)—, —O—, —S—, or —NR^(L3)—; wherein each occurrence ofR^(L3) and R^(L4) is independently hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or acyl;

lxv) L is absent, —C(═O), or a substituted or unsubstitutedC₁₋₆alkylidene or C₂₋₆alkenylidene chain wherein up to two non-adjacentmethylene units are independently optionally replaced by —C(═O)—, —CO₂—,—C(═O)C(═O)—, —C(═O)NR^(L3)—, —OC(═O)—, —OC(═O)NR^(L3)—,—NR^(L3)NR^(L4)—, —NR^(L3)NR^(L4)C(═O)—, —NR^(L3)C(═O)—, —NR^(L3)CO₂—,—NR^(L3)C(═O)NR^(L4)—, —S(═O)—, —SO₂—, —NR^(L3)SO₂—, —SO₂NR^(L3)—,—NR^(L3)SO₂NR^(L4)—, —O—, —S—, or —NR^(L3)—; wherein each occurrence ofR^(L3) and R^(L4) is independently hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or acyl;

lxvi) L is absent;

lxvii) L is —C(═O);

lxviii) L is absent, —C(═O), —CH₂C(═O)NH—, —CH₂NH—C(═O)—, —O—CH₂—C(═O)—,—CH₂—CH₂—C(═O)—, —CH═CH—C(═O)NH—CH₂—, —CH(OH)—CH₂—O—,—CH(OH)—CH₂—N(CH₃)—, —CH(OH)—CH₂—CH₂—, —CH₂—CH₂—CH(OH)—, —O—CH₂—CH(OH)—,—O—CH₂—CH(OH)—CH₂—, —O—CH₂—CH₂—CH(OH)—, O—CH₂—CH₂—O—, —CH₂—CH₂—CH₂—O—,—CH₂—CH(OH)—CH₂—O, —CH₂—CH₂—O—, —CH—(CH₃)—NH—C(═O)—, —CH₂—NH—SO₂—,—NH—SO₂—CH₂—, —CH₂—SO₂—NH—, —SO₂NH—CH₂—, —C(═O)—NH—C(═O)—,—NH—C(═O)—NH—, —NH—C(═O)—NH—CH₂—, —CH₂—NH—C(═O)—NH—,—C(═O)—NH—CH₂—C(═O)—NH, —NH—C(═O)—O—, or —O—C(═O)—NH—;

lxix) L is —(CH₂)_(q)— wherein q is 1-5;

lxx) L is —CH₂—;

lxxi) L is —(CH₂)₃—;

lxxii) L is a moiety having the structure:

lxxii) AR¹ is one of the following structures:

wherein each occurrence of r is an integer from 0-6; X₁, X₂, X₃ and X₄are each independently N or CR^(Q1); AR₃ is a heterocyclic, aryl orheteroaryl moiety; each occurrence of R^(Q1) is independently hydrogen,OR^(Q3), OCF₃, SR^(Q3), halogen, CN, isocyanate, NO₂, CF₃,NR^(Q3Q)R^(Q4), —SO₂R^(Q3), alkyl-NR^(Q3)R^(Q4),alkyl-C(═O)—NR^(Q3)R^(Q4), alkyl-C(═O)R^(Q3), or an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety,wherein each occurrence of R^(Q3) and R^(Q4) is independently hydrogen,a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroarylmoiety; and R^(Q2) is hydrogen, an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or anitrogen protecting group;

lxxiv) AR¹ is one of the following structures:

wherein each occurrence of r is an integer from 0-6; X₁, X₂, X₃ and X₄is independently N or CR^(Q1); X₅ is O, S or NR^(Q2); AR³ is aheterocyclic, aryl or heteroaryl moiety; each occurrence of R^(Q1) isindependently hydrogen, OR^(Q3), OCF₃, SR^(Q3), halogen, CN, isocyanate,NO₂, CF₃, NR^(Q3Q)R^(Q4), —SO₂R^(Q3), alkyl-NR^(Q3)R^(Q4),alkyl-C(═O)—NR^(Q3)R^(Q4), alkyl-C(═O)R^(Q3), or an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety,wherein each occurrence of R^(Q3) and R^(Q4) is independently hydrogen,a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroarylmoiety; and R^(Q2) is hydrogen, an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or anitrogen protecting group;

lxxv) AR¹ is one of the following structures:

wherein r is as defined above; X₁, X₂, X₃ and X₄ is independently N orCH; X₅ is CHR^(Q1) or NH; each occurrence of R^(Q1) is independentlyhydrogen, OR^(Q3), OCF₃, SR^(Q3), halogen, CN, isocyanate, NO₂, CF₃,NR^(Q3Q)R^(Q4), —SO₂R^(Q3), alkyl-NR^(Q3)R^(Q4),alkyl-C(═O)—NR^(Q3)R^(Q4), alkyl-C(═O)R^(Q3), or an aliphatic,alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety,wherein each occurrence of R^(Q3) and R^(Q4) is independently hydrogen,a protecting group, or an aliphatic, heteroaliphatic, aryl or heteroarylmoiety; and R^(Q2) is hydrogen, an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroaryl moiety or anitrogen protecting group;

lxxvi) AR¹ is one of the following structures:

wherein X⁰ is F or Cl; X₂ is N or CR^(Q1); X₅ is CH, O, S or NH; R^(Q1)is hydrogen, methyl, —CF₃, —OCH₃, —OCF₃ or halogen;

lxxvii) AR¹ is one of the following structures:

lxxviii) AR¹ is one of the following structures:

lxxix) AR¹-L- is one of the following structures:

lxxx) AR¹-L- is one of the following structures:

lxxxi) R⁴, for each occurrence, is independently hydrogen, halogen, —CN,—NO₂, an alkyl, alkylenyl; alkynyl; cycloalkyl, heteroalkyl,heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, oris -GR^(G1) wherein G is —O—, —S—, —NR^(G2)—, —CO—, —SO—, —SO₂—,—C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)— or —SO₂NR^(G2)—, andR^(G1) and R^(G2) are independently hydrogen, an alkyl, alkylenyl;alkynyl; cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety;

lxxxii) R⁴, for each occurrence, is independently hydrogen, halogen, orlower alkyl;

lxxxiii) R⁴, for each occurrence, is independently hydrogen or chloro;

lxxxiv) n is 0;

lxxxv) n is 2;

lxxxvi) n is 2 and each occurrence of R⁴ is a halogen;

lxxxvii) n is 2 and each occurrence of R⁴ is Cl;

lxxxviii) p is 1;

lxxxix) p is 2; and/or

xc) Compounds of formula (II) wherein when —C(═O)NHC(R¹)(R²)R³ has thestructure:

then AR¹ is not one of:

wherein Y¹ is N or CR^(Q1); X¹, X², X³ and X⁴ are independently CR^(Q1);X5 is NR^(Q1), O or S; r is 0-3; and each occurrence of R^(Q1) isindependently CN, NO₂, halogen, CF₃, an alkyl, cycloalkyl, heteroalkyl,heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety oris GR^(G1) wherein G is —O—, —S—, —NR^(G2)—, —CO—, —SO—, —C₀₋₆alkylSO₂—,—C₀₋₆alkylSO₂NR^(G2)—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)— or—NR^(G2)C(═O)—, and R^(G1) and R^(G2) are independently hydrogen, analkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety.

It will be appreciated that for each of the classes and subclassesdescribed above and herein, any one or more occurrences of aliphatic orheteroaliphatic may independently be substituted or unsubstituted,cyclic or acyclic, linear or branched and any one or more occurrences ofaryl, heteroaryl, cycloaliphatic, cycloheteroaliphatic may besubstituted or unsubstituted.

The reader will also appreciate that all possible combinations of thevariables described in i)-through xc) above (e.g., R1, R², R³, R⁴, L,and AR¹, among others) are considered part of the invention. Thus, theinvention encompasses any and all compounds of formula I or II generatedby taking any possible permutation of variables R¹, R², R³, R⁴, L, AR¹,etc. and other variables/substituents (e.g., X¹, X², X³, X⁴, R^(1A),R^(2A), R^(2C), R^(2D), etc.) as further defined for R¹, R², R³, R⁴, L,AR¹, etc. described in i)-through xc) above.

For example, an exemplary combination of variables described ini)-through xc) above includes those compounds of Formula I wherein:

R¹ and R² are each independently hydrogen, an amino acid side chain,—(CH₂)_(m)OH, —(CH₂)_(m)aryl, —(CH₂)_(m)heteroaryl, wherein m is 0-6,—CH(R^(1A))(OR^(1B)), —CH(R^(1A))(NHR^(1B)), U-T-Q, or an aliphatic,alicyclic, heteroaliphatic or heteroalicyclic moiety optionallysubstituted with U-T-Q, wherein U is absent, —O—, —S(O)₀₋₂—,—SO₂N(R^(1A)), —N(R^(1A))—, —N(R^(1A))C(═O)—, —N(R^(1A))C(═O)—O—,—N(R^(1A))C(═O)—N(R^(1B))—, —N(R^(1A))—SO₂—, —C(═O)—, —C(═O)—O—,—O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl,—C(═O)—N(R^(1A))—, —O—C(═O)—N(R^(1A))—, —C(═N—R^(1E))—,—C(═N—R^(1E))—O—, —C(═N—R^(1E))—N(R^(1A))—, —O—C(═N—R^(1E))—N(R^(1A))—,—N(R^(1A))C(═N—R^(1E))—, —N(R^(1A))C(═N—R^(1E))—O—,N(R^(1A))C(═N—R^(1E))—N(R^(1B))—, —P(═O)(OR^(1A))—O—, or—P(═O)(R^(1A))—O—; T is absent, an aliphatic, heteroaliphatic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; and Q is hydrogen,halogen, cyano, isocyanate, —OR^(1B), —SR^(1B); —N(R^(1B))₂,—NHC(═O)OR^(1B), —NHC(═O)N(R^(1B))₂, —NHC(═O)R^(1B), —NHSO₂R^(1B),—NHSO₂N(R^(1B))₂, —NHSO₂NHC(═O)OR^(1B), —NHC(═O)NHSO₂R^(1B),—C(═O)NHC(═O)OR^(1B), —C(═O)NHC(═O)R^(1B), —C(═O)NHC(═O)N(R^(1B))₂,—C(═O)NHSO₂R^(1B), —C(═O)NHSO₂N(R^(1B))₂, —C(═S)N(R^(1B))₂, —SO₂R^(1B),—SO₂—O—R^(1B), —SO₂—N(R^(1B))₂, —SO₂—NHC(═O)OR^(1B),—SO₂—NHC(═O)—N(R^(1B))₂, —SO₂—NHC(═O)R^(1B), —O—C(═O)N(R^(1B))₂,—O—C(═O)R^(1B), —O—C(═O)NHC(═O)R^(1B), —O—C(═O)NH—SO₂R^(1B),—O—SO₂R^(1B), or an aliphatic heteroaliphatic, aryl or heteroarylmoiety, or wherein R¹ and R² taken together are an alicyclic orheterocyclic moiety, or together are

wherein each occurrence of R^(1A) and R^(1B) is independently hydrogen,an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety, —COR^(1C), or—CONR^(1C)R^(1D); wherein each occurrence of R^(1C) and R^(1D) isindependently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic,aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R^(1E) ishydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR^(1C),—NR^(1C)R^(1D) or —SO₂R^(1C);

R³ is —C(═O)OR^(3A), —C(═O)H, —CH₂OR^(3A), —CH₂O—C(═O)-alkyl,—C(═O)NH(R^(3A)), —CH₂X⁰; wherein each occurrence of R^(3A) isindependently hydrogen, a protecting group, an aliphatic, alicyclic,heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl,alkylheteroaryl, heteroalkylaryl or heteroalkylheteroaryl moiety, orR^(3A), taken together with R¹ or R², forms a heterocyclic moiety;wherein X⁰ is a halogen selected from F, Cl, Br or I;

R⁴, for each occurrence, is independently hydrogen, halogen, —CN, —NO₂,an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) whereinG is —O—, —S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—,—OC(═O)—, —NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) areindependently hydrogen, an aliphatic, alicyclic, heteroaliphatic,heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety;

AR¹ is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl,alkylheteroaryl, alicyclic or heterocyclic moiety;

A, B, D and E are connected by either a single or double bond, asvalency permits; wherein each occurrence of A, B, D and E isindependently C═O, CR^(i)R^(ii), NR^(i), CR^(i), N, O, S, S(═O) or SO₂;wherein each occurrence of R^(i) is independently hydrogen, halogen,—CN, —NO₂, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic,aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or is -GR^(G1)wherein G is —O—, —S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—,—C(═O)NR^(G2)—, —OC(═O)—, —NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) andR^(G2) are independently hydrogen, an aliphatic, alicyclic,heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl oralkylheteroaryl moiety, or any two adjacent occurrences of R^(i), takentogether, represent an alicyclic, heteroalicyclic, aryl, or heteroarylmoiety; and

L is absent or is V-W-X-Y-Z, wherein each occurrence of V, W, X, Y and Zis independently absent, C═O, NR^(L1), —O—, —C(R^(L1))═, ═C(R^(L1))—,—C(R^(L1))(R^(L2)), C(═N—O—R^(L1)), C(═N—R^(L1)), —N═, S(O)₀₋₂; asubstituted or unsubstituted C₁₋₆alkylidene or C₂₋₆alkenylidene chainwherein up to two non-adjacent methylene units are independentlyoptionally replaced by —C(═O)—, —CO₂—, —C(═O)C(═O)—, —C(═O)NR^(L3)—,—OC(═O)—, —OC(═O)NR^(L3)—, —NR^(L3)NR^(L4)—, —NR^(L3)NR^(L4)C(═O)—,—NR^(L3)C(═O)—, —NR^(L3)CO₂—, —NR^(L3)C(═O)NR^(L4)—, —S(═O)—, —SO₂—,—NR^(L3)SO₂—, —SO₂NR^(L3)—, —NR^(L3)SO₂NR^(L4)—, —O—, —S—, or —NR^(L3)—;wherein each occurrence of R^(L3) and R^(L4) is independently hydrogen,alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic,alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylarylor alkylheteroaryl moiety; and each occurrence of R^(L1) and R^(L2) isindependently hydrogen, hydroxyl, protected hydroxyl, amino, protectedamino, thio, protected thio, halogen, cyano, isocyanate, carboxy,carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido,thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl,or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or moreoccurrences of R^(L1) and R^(L2), taken together, or taken together withone of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or forman aryl or heteroaryl moiety.

Other exemplary combinations are illustrated by compounds of thefollowing subgroups I through XIV:

I) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(B1), R^(B2) and R^(E) are independently hydrogen orsubstituted or unsubstituted lower alkyL. In certain embodiments, R^(4A)and R^(4B) are each CL. In yet other embodiments, one of R^(B1) andR^(B2) is hydrogen, the other is substituted or unsubstituted loweralkyL. In certain exemplary embodiments, R^(B1) and R^(B2) are eachhydrogen. In certain other exemplary embodiments, R^(B1) and R^(B2) areeach lower alkyL. In certain exemplary embodiments, R^(B1) and R^(B2)are each methyL. In other embodiments, R^(E) is hydrogen. In yet otherembodiments, R^(E) is substituted or unsubstituted lower alkyL. In yetother embodiments, R^(E) is substituted or unsubstituted methyl, ethyl,propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl,tert-pentyl or n-hexyL. In certain embodiments, R^(4A) and R^(4B) areeach Cl; and R^(B1) and R^(B2) are each hydrogen.

II) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(E) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In otherembodiments, R^(E) is hydrogen. In yet other embodiments, R^(E) issubstituted or unsubstituted lower alkyL. In yet other embodiments,R^(E) is substituted or unsubstituted methyl, ethyl, propyl, i-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl orn-hexyl.

III) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(E) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In otherembodiments, R^(E) is hydrogen. In yet other embodiments, R^(E) issubstituted or unsubstituted lower alkyL. In yet other embodiments,R^(E) is substituted or unsubstituted methyl, ethyl, propyl, i-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl orn-hexyl.

IV) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(E) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In otherembodiments, R^(E) is hydrogen. In yet other embodiments, R^(E) issubstituted or unsubstituted lower alkyL. In yet other embodiments,R^(E) is substituted or unsubstituted methyl, ethyl, propyl, i-propyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl orn-hexyl.

V) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; R^(A) is hydrogen, lower alkyl or acyl; and R^(E) ishydrogen or substituted or unsubstituted lower alkyL. In certainembodiments, R^(4A) and R^(4B) are each CL. In other embodiments, R^(E)is hydrogen. In yet other embodiments, R^(E) is substituted orunsubstituted lower alkyL. In yet other embodiments, R^(E) issubstituted or unsubstituted methyl, ethyl, propyl, i-propyl, n-butyl,sec-butyl, tert-butyl, n-pentyl, sec-pentyl, tert-pentyl or n-hexyl.

VI) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; R^(A1), R^(A2), R^(B1) and R^(B2) are independentlyhydrogen or substituted or unsubstituted lower alkyL. In certainembodiments, R^(4A) and R^(4B) are each CL. In certain embodiments,R^(A1), R^(A2), R^(B1) And R^(B2) are each hydrogen.

VII) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(A) and R^(B) are independently hydrogen orsubstituted or unsubstituted lower alkyL. In certain embodiments, R^(4A)and R^(4B) are each CL. In certain embodiments, R^(A) and R^(B) are eachhydrogen.

VIII) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(A) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In certainembodiments, R^(A) is hydrogen.

IX) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(B) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In certainembodiments, R^(B) is hydrogen.

X) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and R^(A) is hydrogen or substituted or unsubstituted loweralkyL. In certain embodiments, R^(4A) and R^(4B) are each CL. In certainembodiments, R^(A) is hydrogen.

XI) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; R^(A), R^(B) and R^(E) are independently hydrogen orsubstituted or unsubstituted lower alkyL. In certain embodiments, R^(4A)and R^(4B) are each CL. In certain embodiments, R^(A) and R^(B) are eachhydrogen. In certain other embodiments, R^(E) is hydrogen. In yet otherembodiments, R^(A), R^(B) and R^(E) are each hydrogen.

XII) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; R^(A), R^(B) and R^(E) are independently hydrogen orsubstituted or unsubstituted lower alkyL. In certain embodiments, R^(4A)and R^(4B) are each CL. In certain embodiments, R^(A) and R^(B) are eachhydrogen. In certain other embodiments, R^(E) is hydrogen. In yet otherembodiments, R^(A), R^(B) and R^(E) are each hydrogen.

XIII) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and A and B are independently N or CH. In certainembodiments, R^(4A) and R^(4B) are each CL. In certain embodiments, A isN. In certain embodiments, A is CH. In certain embodiments, B is N. Incertain embodiments, A is CH. In certain embodiments, A and B are eachN. In certain embodiments, A is CH. In certain embodiments, A and B areeach CH.

XIV) Compounds Having the Structure (and Pharmaceutically AcceptableDerivatives Thereof):

wherein R^(4A) and R^(4B) are independently a halogen selected from F,Cl, Br or I; and A and B are independently N or CH. In certainembodiments, R^(4A) and R^(4B) are each CL. In certain embodiments, A isN. In certain embodiments, A is CH. In certain embodiments, B is N. Incertain embodiments, A is CH. In certain embodiments, A and B are eachN. In certain embodiments, A is CH. In certain embodiments, A and B areeach CH.

In certain embodiments, for compounds of classes I-XIV above, AR¹-L- isa moiety having one of the following structures:

and —C(═O)NHC(R¹)(R²)R³ is a moiety having one of the followingstructures:

or bioisosteres thereof;

wherein R^(2A) and R^(3A) are as defined in classes and subclassesherein; and R^(2D) is a moiety having one of the following structures:

wherein s is an integer between 0 and 6; each occurrence of R^(P1) isindependently hydrogen, halogen, CN, isocyanate, NO₂, —P(═O)(YR^(P5))₂,an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl, heteroaryl,alkylaryl or alkylheteroaryl moiety, or is -GR^(G1) wherein G is —O—,—S—, —NR^(G2)—, —CO—, —SO—, —SO₂—, —C(═O)O—, —C(═O)NR^(G2)—, —OC(═O)—,—NR^(G2)C(═O)— or —SO₂NR^(G2)—, and R^(G1) and R^(G2) are independentlyhydrogen, an alkyl, cycloalkyl, heteroalkyl, heterocyclic, aryl,heteroaryl, alkylaryl or alkylheteroaryl moiety; each occurrence of Y isindependently a bond or O; each occurrence of R^(P5) is independentlyalkyl, heteroalkyl, aryl or heteroaryl, or when Y is O R^(P5) may alsobe hydrogen; and each occurrence of R^(P5) is independently hydrogen, analiphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl,alkylaryl, alkylheteroaryl, heteroalkylaryl, or heteroalkylheteroarylmoiety or a nitrogen protecting group; wherein any two adjacentoccurrences of R^(P1) and R^(P2), taken together, may form a cycloalkyl,heterocyclic, aryl or heteroaryl moiety.

In certain embodiments, R^(2A) and R^(3A) are each hydrogen.

In certain embodiments, R^(2D) is a moiety having one of the structures:

wherein each occurrence of R^(P1) is independently hydrogen, halogen,methyl, —OCH₃, —OH, —NH₂, —NHCH₃, or —N(CH₃)₂.

In certain embodiments, R^(2D) is a moiety having one of the structures:

It will also be appreciated that for each of the subgroups I-XIVdescribed above, a variety of other subclasses are of special interest,including, but not limited to those classes described above i)-xc) andclasses, subclasses and species of compounds described above and in theexamples herein.

Some of the foregoing compounds can comprise one or more asymmetriccenters, and thus can exist in various isomeric forms, e.g.,stereoisomers and/or diastereomers. Thus, inventive compounds andpharmaceutical compositions thereof may be in the form of an individualenantiomer, diastereomer or geometric isomer, or may be in the form of amixture of stereoisomers. In certain embodiments, the compounds of theinvention are enantiopure compounds. In certain other embodiments,mixtures of stereoisomers or diastereomers are provided.

Furthermore, certain compounds, as described herein may have one or moredouble bonds that can exist as either the Z or E isomer, unlessotherwise indicated. The invention additionally encompasses thecompounds as individual isomers substantially free of other isomers andalternatively, as mixtures of various isomers, e.g., racemic mixtures ofstereoisomers. In addition to the above-mentioned compounds per se, thisinvention also encompasses pharmaceutically acceptable derivatives ofthese compounds and compositions comprising one or more compounds of theinvention and one or more pharmaceutically acceptable excipients oradditives.

Compounds of the invention may be prepared by crystallization ofcompound of formula (I) or (II) under different conditions and may existas one or a combination of polymorphs of compound of general formula (I)or (II) forming part of this invention. For example, differentpolymorphs may be identified and/or prepared using different solvents,or different mixtures of solvents for recrystallization; by performingcrystallizations at different temperatures; or by using various modes ofcooling, ranging from very fast to very slow cooling duringcrystallizations. Polymorphs may also be obtained by heating or meltingthe compound followed by gradual or fast cooling. The presence ofpolymorphs may be determined by solid probe NMR spectroscopy, IRspectroscopy, differential scanning calorimetry, powder X-raydiffractogram and/or other techniques. Thus, the present inventionencompasses inventive compounds, their derivatives, their tautomericforms, their stereoisomers, their polymorphs, their pharmaceuticallyacceptable salts their pharmaceutically acceptable solvates andpharmaceutically acceptable compositions containing them.

2) Pharmaceutical Compositions

As discussed above this invention provides novel compounds that havebiological properties useful for the treatment of Mac-1 and LFA-1mediated disorders.

Accordingly, in another aspect of the present invention, pharmaceuticalcompositions are provided, which comprise any one of the compoundsdescribed herein (or a prodrug, pharmaceutically acceptable salt orother pharmaceutically acceptable derivative thereof), and optionallycomprise a pharmaceutically acceptable carrier. In certain embodiments,these compositions optionally further comprise one or more additionaltherapeutic agents. Alternatively, a compound of this invention may beadministered to a patient in need thereof in combination with theadministration of one or more other therapeutic agents. For example,additional therapeutic agents for conjoint administration or inclusionin a pharmaceutical composition with a compound of this invention may bean approved anti-inflammatory agent, or it may be any one of a number ofagents undergoing approval in the Food and Drug Administration thatultimately obtain approval for the treatment of any disorder mediated byMac-1 or LFA-1. It will also be appreciated that certain of thecompounds of present invention can exist in free form for treatment, orwhere appropriate, as a pharmaceutically acceptable derivative thereof.

As described above, the pharmaceutical compositions of the presentinvention additionally comprise a pharmaceutically acceptable carrier,which, as used herein, includes any and all solvents, diluents, or otherliquid vehicle, dispersion or suspension aids, surface active agents,isotonic agents, thickening or emulsifying agents, preservatives, solidbinders, lubricants and the like, as suited to the particular dosageform desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses variouscarriers used in formulating pharmaceutical compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutical composition, its use is contemplatedto be within the scope of this invention. Some examples of materialswhich can serve as pharmaceutically acceptable carriers include, but arenot limited to, sugars such as lactose, glucose and sucrose; starchessuch as corn starch and potato starch; cellulose and its derivativessuch as sodium carboxymethyl cellulose, ethyl cellulose and celluloseacetate; powdered tragacanth; malt; gelatine; talc; excipients such ascocoa butter and suppository waxes; oils such as peanut oil, cottonseedoil; safflower oil, sesame oil; olive oil; corn oil and soybean oil;glycols; such as propylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother non-toxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanedioL. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a drug, it is often desirable to slowthe absorption of the drug from subcutaneous or intramuscular injection.This may be accomplished by the use of a liquid suspension orcrystalline or amorphous material with poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionthat, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle. Injectable depot forms are made by forming microencapsulematrices of the drug in biodegradable polymers such aspolylactide-polyglycolide. Depending upon the ratio of drug to polymerand the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude (poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose and starch. Such dosage forms may alsocomprise, as in normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such asmagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes.

The present invention encompasses pharmaceutically acceptable topicalformulations of inventive compounds. The term “pharmaceuticallyacceptable topical formulation”, as used herein, means any formulationwhich is pharmaceutically acceptable for intradermal administration of acompound of the invention by application of the formulation to theepidermis. In certain embodiments of the invention, the topicalformulation comprises a carrier system. Pharmaceutically effectivecarriers include, but are not limited to, solvents (e.g., alcohols, polyalcohols, water), creams, lotions, ointments, oils, plasters, liposomes,powders, emulsions, microemulsions, and buffered solutions (e.g.,hypotonic or buffered saline) or any other carrier known in the art fortopically administering pharmaceuticals. A more complete listing ofarT-known carriers is provided by reference texts that are standard inthe art, for example, Remington's Pharmaceutical Sciences, 16th Edition,1980 and 17th Edition, 1985, both published by Mack Publishing Company,Easton, Pa., the disclosures of which are incorporated herein byreference in their entireties. In certain other embodiments, the topicalformulations of the invention may comprise excipients. Anypharmaceutically acceptable excipient known in the art may be used toprepare the inventive pharmaceutically acceptable topical formulations.Examples of excipients that can be included in the topical formulationsof the invention include, but are not limited to, preservatives,antioxidants, moisturizers, emollients, buffering agents, solubilizingagents, other penetration agents, skin protectants, surfactants, andpropellants, and/or additional therapeutic agents used in combination tothe inventive compound. Suitable preservatives include, but are notlimited to, alcohols, quaternary amines, organic acids, parabens, andphenols. Suitable antioxidants include, but are not limited to, ascorbicacid and its esters, sodium bisulfite, butylated hydroxytoluene,butylated hydroxyanisole, tocopherols, and chelating agents like EDTAand citric acid. Suitable moisturizers include, but are not limited to,glycerine, sorbitol, polyethylene glycols, urea, and propylene glycoL.Suitable buffering agents for use with the invention include, but arenot limited to, citric, hydrochloric, and lactic acid buffers. Suitablesolubilizing agents include, but are not limited to, quaternary ammoniumchlorides, cyclodextrins, benzyl benzoate, lecithin, and polysorbates.Suitable skin protectants that can be used in the topical formulationsof the invention include, but are not limited to, vitamin E oil,allatoin, dimethicone, glycerin, petrolatum, and zinc oxide.

In certain embodiments, the pharmaceutically acceptable topicalformulations of the invention comprise at least a compound of theinvention and a penetration enhancing agent. The choice of topicalformulation will depend or several factors, including the condition tobe treated, the physicochemical characteristics of the inventivecompound and other excipients present, their stability in theformulation, available manufacturing equipment, and costs constraints.As used herein the term “penetration enhancing agent” means an agentcapable of transporting a pharmacologically active compound through thestratum corneum and into the epidermis or dermis, preferably, withlittle or no systemic absorption. A wide variety of compounds have beenevaluated as to their effectiveness in enhancing the rate of penetrationof drugs through the skin. See, for example, Percutaneous PenetrationEnhancers, Maibach H. I. and Smith H. E. (eds.), CRC Press, Inc., BocaRaton, Fla. (1995), which surveys the use and testing of various skinpenetration enhancers, and Buyuktimkin et al., Chemical Means ofTransdermal Drug Permeation Enhancement in Transdermal and Topical DrugDelivery Systems, Gosh T. K., Pfister W. R., Yum S. I. (Eds.),Interpharm Press Inc., Buffalo Grove, Ill. (1997). In certain exemplaryembodiments, penetration agents for use with the invention include, butare not limited to, triglycerides (e.g., soybean oil), aloe compositions(e.g., aloe-vera gel), ethyl alcohol, isopropyl alcohol,octolyphenylpolyethylene glycol, oleic acid, polyethylene glycol 400,propylene glycol, N-decylmethylsulfoxide, fatty acid esters (e.g.,isopropyl myristate, methyl laurate, glycerol monooleate, and propyleneglycol monooleate) and N-methyl pyrrolidone.

In certain embodiments, the compositions may be in the form ofointments, pastes, creams, lotions, gels, powders, solutions, sprays,inhalants or patches. In certain exemplary embodiments, formulations ofthe compositions according to the invention are creams, which mayfurther contain saturated or unsaturated fatty acids such as stearicacid, palmitic acid, oleic acid, palmito-oleic acid, cetyl or oleylalcohols, stearic acid being particularly preferred. Creams of theinvention may also contain a non-ionic surfactant, for example,polyoxy-40-stearate. In certain embodiments, the active component isadmixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are made by dissolving or dispensing thecompound in the proper medium. As discussed above, penetration enhancingagents can also be used to increase the flux of the compound across theskin. The rate can be controlled by either providing a rate controllingmembrane or by dispersing the compound in a polymer matrix or gel.

It will also be appreciated that the compounds and pharmaceuticalcompositions of the present invention can be formulated and employed incombination therapies, that is, the compounds and pharmaceuticalcompositions can be formulated with or administered concurrently with,prior to, or subsequent to, one or more other desired therapeutics ormedical procedures. The particular combination of therapies(therapeutics or procedures) to employ in a combination regimen willtake into account compatibility of the desired therapeutics and/orprocedures and the desired therapeutic effect to be achieved. It willalso be appreciated that the therapies employed may achieve a desiredeffect for the same disorder (for example, an inventive compound may beadministered concurrently with another anti-inflammatory agent), or theymay achieve different effects (e.g., control of any adverse effects).

In certain embodiments, the pharmaceutical compositions of the presentinvention further comprise one or more additional therapeutically activeingredients (e.g., anti-inflammatory and/or palliative). For purposes ofthe invention, the term “Palliative” refers to treatment that is focusedon the relief of symptoms of a disease and/or side effects of atherapeutic regimen, but is not curative. For example, palliativetreatment encompasses painkillers, antinausea medications andanti-sickness drugs.

3) Research Uses, Pharmaceutical Uses and Methods of Treatment

Research Uses

According to the present invention, the inventive compounds may beassayed in any of the available assays known in the art for identifyingcompounds having the ability to modulate adhesion between intracellularadhesion molecules and the leukocyte integrin family of receptors; toantagonize CD11/CD18 receptors associated with leukocytes and/or toantagonize Mac-1 and/or LFA-1. For example, the assay may be cellular ornon-cellular, in vivo or in vitro, high- or low-throughput format, etc.

Thus, in one aspect, compounds of this invention which are of particularinterest include those which:

-   -   modulate adhesion between intracellular adhesion molecules        (e.g., ICAM-1, -2 and -3) and the leukocyte integrin family of        receptors;    -   exhibit the ability to antagonize CD11/CD18 receptors associated        with leukocytes;    -   exhibit the ability to antagonize Mac-1 and/or LFA-1; and    -   are useful for the treatment of LFA-1 mediated disorders.

As detailed in the exemplification herein, in assays to determine theability of compounds to modulate T-cell adhesion to 5dICAM-Ig (e.g.,cell attachment assay), certain inventive compounds exhibited IC₅₀values≦50 μM. In certain other embodiments, inventive compounds exhibitIC₅₀ values≦40 μM. In certain other embodiments, inventive compoundsexhibit IC₅₀ values≦30 μM. In certain other embodiments, inventivecompounds exhibit IC₅₀ values≦20 μM. In certain other embodiments,inventive compounds exhibit IC₅₀ values≦10 μM. In certain otherembodiments, inventive compounds exhibit IC₅₀ values≦7.5 μM. In certainembodiments, inventive compounds exhibit IC₅₀ values≦5 μM. In certainother embodiments, inventive compounds exhibit IC₅₀ values≦2.5 μM. Incertain embodiments, inventive compounds exhibit IC₅₀ values≦1 μM. Incertain other embodiments, inventive compounds exhibit IC₅₀ values≦750nM. In certain other embodiments, inventive compounds exhibit IC₅₀values≦500 nM. In certain other embodiments, inventive compounds exhibitIC₅₀ values≦250 nM. In certain other embodiments, inventive compoundsexhibit IC₅₀ values≦100 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦75 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦50 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦40 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦30 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦20 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦10 nM. In other embodiments, exemplary compoundsexhibited IC₅₀ values≦5 nM.

Pharmaceutical Uses and Methods of Treatment

As discussed above, certain of the compounds as described herein exhibitactivity generally as modulators of adhesion between intracellularadhesion molecules. More specifically, compounds of the inventiondemonstrate the ability to antagonize CD11/CD18 receptors associatedwith leukocytes and in certain embodiments exhibit the ability toantagonize LFA-1 interactions. Thus, in certain embodiments, compoundsof the invention are useful for the treatment of LFA-1 mediateddisorders.

Accordingly, in another aspect of the invention, methods for treating(or preventing) of LFA-1 mediated disorders are provided comprisingadministering a therapeutically effective amount of a compound offormula (I) or (II) as described herein, to a subject in need thereof.In certain embodiments, a method for the treatment of LFA-1 mediateddisorders is provided comprising administering a therapeuticallyeffective amount of an inventive compound, or a pharmaceuticalcomposition comprising an inventive compound to a subject in needthereof, in such amounts and for such time as is necessary to achievethe desired result.

In certain embodiments, the method involves the administration of atherapeutically effective amount of the compound or a pharmaceuticallyacceptable derivative thereof to a subject (including, but not limitedto a human or animal) in need of it.

As discussed above this invention provides novel compounds that havebiological properties useful for the treatment of Mac-1 and/or LFA-1mediated disorders. In certain embodiments, the inventive compounds asuseful for the treatment of psoriasis, responses associated withinflammatory bowel disease (such as Crohn's disease and ulcerativecolitis), dermatitis, meningitis, encephalitis, uveitis, allergicconditions such as eczema and asthma, conditions involving infiltrationof T-cells and chronic inflammatory responses, skin hypersensitivityreactions (including poison ivy and poison oak), artherosclerosis,autoimmune diseases such as rheumatoid arthritis, systemic lupuserythematosus (SLE), diabetes mellitus, multiple sclerosis, Reynaud'ssyndrome, autoimmune thyroiditis, experimental autoimmuneencephalomyelitis, Sjorgen's syndrome, juvenile onset diabetes andimmune responses associated with delayed hypersensitivity mediated bycytokines and T-lymphocytes typically found in tuberculosis,sarcoidosis, polymyositis, granulomatosis and vasculitis, perniciousanemia, diseases involving leukocyte diapedeses, CNS inflammatorydisorder, multiple organ injury syndrome secondary to septicaemia ortrauma, autoimmune hemolytic anemia, myasthenia gravis, antigen-antibodycomplex mediated diseases, all types of transplantations, includinggraft versus host or host versus graft disease, HIV and rhinovirusinfection, and pulmonary fibrosis to name a few.

As described in more detail herein, in general, compounds of theinvention are useful as antagonists of the interaction betweenintracellular adhesion molecules (e.g., ICAM-1, 2 or 3) and theleukocyte integrin family of receptors. Thus, in certain embodiments,the present invention provides compounds useful for the treatment ofdisorders mediated by the CD11/CD18 family of cellular adhesionmolecules. In certain embodiments of special interest, the presentinvention provides compounds useful for the treatment of disordersmediated by Mac-1 and/or LFA-1. For example, compounds of the inventionare particularly useful for the treatment inflammatory disorders, organgraft rejection and autoimmune disorders, to name a few.

Thus, as described above, in another aspect of the invention, a methodfor the treatment of disorders mediated by the CD11/CD18 family ofcellular adhesion molecules is provided comprising administering atherapeutically effective amount of a compound of formula (I) or (II) asdescribed herein, to a subject in need thereof. In certain embodimentsof special interest the inventive method is used for the treatment ofdisorders mediated by Mac-1 or LFA-1. It will be appreciated that thecompounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for the treatment of disorders mediated by theCD11/CD18 family of cellular adhesion molecules. For example, in certainexemplary embodiments, compounds of the invention are useful asantagonists of the interaction between Mac-1 or LFA-1 and intracellularadhesion molecules (e.g., ICAM-1) and thus the compounds are useful forthe treatment of LFA-1 mediated disorders including, but not limited to,psoriasis, responses associated with inflammatory bowel disease (such asCrohn's disease and ulcerative colitis), dermatitis, meningitis,encephalitis, uveitis, allergic conditions such as eczema and asthma,conditions involving infiltration of T-cells and chronic inflammatoryresponses, skin hypersensitivity reactions (including poison ivy andpoison oak), atherosclerosis, autoimmune diseases such as rheumatoidarthritis, systemic lupus erythematosus (SLE), diabetes mellitus,multiple sclerosis, Reynaud's syndrome, autoimmune thyroiditis,experimental autoimmune encephalomyelitis, Sjorgen's syndrome, juvenileonset diabetes, and immune responses associated with delayedhypersensitivity mediated by cytokines and T-lymphocytes typically foundin tuberculosis, sarcoidosis, polymyositis, granulomatosis andvasculitis, pernicious anemia, diseases involving leukocyte diapedesis,CNS inflammatory disorder, multiple organ injury syndrome secondary tosepticaemia or trauma, autoimmune hemolytic anemia, myasthenia gravis,antigen-antibody complex mediated diseases, all types oftransplantations, including graft versus host or host versus graftdisease, HIV and rhinovirus infection, pulmonary fibrosis and the like,to name a few. Thus, the expression “effective amount” as used herein,refers to a sufficient amount of agent to antagonize the interactionbetween intracellular adhesion molecules (e.g., ICAM) and the leukocyteintegrin family of receptors, and to exhibit a therapeutic effect. Theexact amount required will vary from subject to subject, depending onthe species, age, and general condition of the subject, the severity ofthe infection, the particular therapeutic agent, its mode ofadministration, and the like. The compounds of the invention arepreferably formulated in dosage unit form for ease of administration anduniformity of dosage. The expression “dosage unit form” as used hereinrefers to a physically discrete unit of therapeutic agent appropriatefor the patient to be treated. It will be understood, however, that thetotal daily usage of the compounds and compositions of the presentinvention will be decided by the attending physician within the scope ofsound medical judgment. The specific therapeutically effective doselevel for any particular patient or organism will depend upon a varietyof factors including the disorder being treated and the severity of thedisorder; the activity of the specific compound employed; the specificcomposition employed; the age, body weight, general health, sex and dietof the patient; the time of administration, route of administration, andrate of excretion of the specific compound employed; the duration of thetreatment; drugs used in combination or coincidental with the specificcompound employed; and like factors well known in the medical arts (see,for example, Goodman and Gilman's, “The Pharmacological Basis ofTherapeutics”, Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference in its entirety).

Another aspect of the invention relates to a method for inhibiting theinteraction between LFA-1 and ICAM-1 in a biological sample or apatient, which method comprises administering to the patient, orcontacting said biological sample with a compound of formula I or II ora composition comprising said compound.

Another aspect of the invention relates to a method for inhibiting theCD11a and/or CD18 interaction with ICAM-1, ICAM-2 or ICAM-3 in abiological sample or a patient, which method comprises administering tothe patient, or contacting said biological sample with a compound offormula I or II or a composition comprising said compound.

Furthermore, after formulation with an appropriate pharmaceuticallyacceptable carrier in a desired dosage, the pharmaceutical compositionsof this invention can be administered to humans and other animalsorally, rectally, parenterally, intracisternally, intravaginally,intraperitoneally, topically (as by powders, ointments, or drops),bucally, as an oral or nasal spray, or the like, depending on theseverity of the infection being treated. In certain embodiments, thecompounds of the invention may be administered at dosage levels of about0.001 mg/kg to about 50 mg/kg, from about 0.01 mg/kg to about 25 mg/kg,or from about 0.1 mg/kg to about 10 mg/kg of subject body weight perday, one or more times a day, to obtain the desired therapeutic effect.It will also be appreciated that dosages smaller than 0.001 mg/kg orgreater than 50 mg/kg (for example 50-100 mg/kg) can be administered toa subject. In certain embodiments, compounds are administered orally orparenterally.

TREATMENT KIT

In other embodiments, the present invention relates to a kit forconveniently and effectively carrying out the methods in accordance withthe present invention. In general, the pharmaceutical pack or kitcomprises one or more containers filled with one or more of theingredients of the pharmaceutical compositions of the invention. Suchkits are especially suited for the delivery of solid oral forms such astablets or capsules. Such a kit preferably includes a number of unitdosages, and may also include a card having the dosages oriented in theorder of their intended use. If desired, a memory aid can be provided,for example in the form of numbers, letters, or other markings or with acalendar insert, designating the days in the treatment schedule in whichthe dosages can be administered. Alternatively, placebo dosages, orcalcium dietary supplements, either in a form similar to or distinctfrom the dosages of the pharmaceutical compositions, can be included toprovide a kit in which a dosage is taken every day. Optionallyassociated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use or sale ofpharmaceutical products, which notice reflects approval by the agency ofmanufacture, use or sale for human administration.

EQUIVALENTS

The representative examples that follow are intended to help illustratethe invention, and are not intended to, nor should they be construed to,limit the scope of the invention. Indeed, various modifications of theinvention and many further embodiments thereof, in addition to thoseshown and described herein, will become apparent to those skilled in theart from the full contents of this document, including the exampleswhich follow and the references to the scientific and patent literaturecited herein. It should further be appreciated that the contents ofthose cited references are incorporated herein by reference to helpillustrate the state of the art.

The following examples contain important additional information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and the equivalents thereof.

EXEMPLIFICATION

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

1) General Description of Synthetic Methods:

The practitioner has a well-established literature of macrolidechemistry to draw upon, in combination with the information containedherein, for guidance on synthetic strategies, protecting groups, andother materials and methods useful for the synthesis of the compounds ofthis invention.

The various references cited herein provide helpful backgroundinformation on preparing compounds similar to the inventive compoundsdescribed herein or relevant intermediates, as well as information onformulation, uses, and administration of such compounds which may be ofinterest.

Moreover, the practitioner is directed to the specific guidance andexamples provided in this document relating to various exemplarycompounds and intermediates thereof.

The compounds of this invention and their preparation can be understoodfurther by the examples that illustrate some of the processes by whichthese compounds are prepared or used. It will be appreciated, however,that these examples do not limit the invention. Variations of theinvention, now known or further developed, are considered to fall withinthe scope of the present invention as described herein and ashereinafter claimed.

According to the present invention, any available techniques can be usedto make or prepare the inventive compounds or compositions includingthem. For example, a variety of solution phase synthetic methods such asthose discussed in detail below may be used. Alternatively oradditionally, the inventive compounds may be prepared using any of avariety combinatorial techniques, parallel synthesis and/or solid phasesynthetic methods known in the art.

It will be appreciated as described below, that a variety of inventivecompounds can be synthesized according to the methods described herein.The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCompany (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis,Mo.), or are prepared by methods well known to a person of ordinaryskill in the art following procedures described in such references asFieser and Fieser 1991, “Reagents for Organic Synthesis”, vols 1-17,John Wiley and Sons, New York, N.Y., 1991; Rodd 1989 “Chemistry ofCarbon Compounds”, vols. 1-5 and supps, Elsevier Science Publishers,1989; “Organic Reactions”, vols 1-40, John Wiley and Sons, New York,N.Y., 1991; March 2001, “Advanced Organic Chemistry”, 5th ed. John Wileyand Sons, New York, N.Y.; and Larock 1990, “Comprehensive OrganicTransformations: A Guide to Functional Group Preparations”, 2nd ed. VCHPublishers. These schemes are merely illustrative of some methods bywhich the compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to aperson of ordinary skill in the art having regard to this disclosure.

The starting materials, intermediates, and compounds of this inventionmay be isolated and purified using conventional techniques, includingfiltration, distillation, crystallization, chromatography, and the like.They may be characterized using conventional methods, including physicalconstants and spectral data.

General Reaction Procedures:

Unless mentioned specifically, reaction mixtures were stirred using amagnetically driven stirrer bar. An inert atmosphere refers to eitherdry argon or dry nitrogen. Reactions were monitored either by thin layerchromatography, by proton nuclear magnetic resonance (NMR) or byhigh-pressure liquid chromatography (HPLC), of a suitably worked upsample of the reaction mixture.

General Work Up Procedures:

Unless mentioned specifically, reaction mixtures were cooled to roomtemperature or below then quenched, when necessary, with either water ora saturated aqueous solution of ammonium chloride. Desired products wereextracted by partitioning between water and a suitable water-immisciblesolvent (e.g. ethyl acetate, dichloromethane, diethyl ether). Thedesired product containing extracts were washed appropriately with waterfollowed by a saturated solution of brine. On occasions where theproduct containing extract was deemed to contain residual oxidants, theextract was washed with a 10% solution of sodium sulphite in saturatedaqueous sodium bicarbonate solution, prior to the aforementioned washingprocedure. On occasions where the product containing extract was deemedto contain residual acids, the extract was washed with saturated aqueoussodium bicarbonate solution, prior to the aforementioned washingprocedure (except in those cases where the desired product itself hadacidic character). On occasions where the product containing extract wasdeemed to contain residual bases, the extract was washed with 10%aqueous citric acid solution, prior to the aforementioned washingprocedure (except in those cases where the desired product itself hadbasic character). Post washing, the desired product containing extractswere dried over anhydrous magnesium sulphate, and then filtered. Thecrude products were then isolated by removal of solvent(s) by rotaryevaporation under reduced pressure, at an appropriate temperature(generally less than 45° C.).

General Purification Procedures:

Unless mentioned specifically, chromatographic purification refers toflash column chromatography on silica, using a single solvent or mixedsolvent as eluent. Suitably purified desired product containing eluteswere combined and concentrated under reduced pressure at an appropriatetemperature (generally less than 45° C.) to constant mass. Finalcompounds were dissolved in 50% aqueous acetonitrile, filtered andtransferred to vials, then freeze-dried under high vacuum beforesubmission for biological testing.

1) Synthesis of Exemplary Compounds:

Unless otherwise indicated, starting materials are either commerciallyavailable or readily accessibly through laboratory synthesis by anyonereasonably familiar with the art. Described generally below, areprocedures and general guidance for the synthesis of compounds asdescribed generally and in subclasses and species herein. In addition,synthetic guidance can be found in published PCT applications WO99/49856 and WO 02/059114, the entire contents of which are herebyincorporated by reference.

Example 1

This example describes the synthesis of

which was prepared according to Scheme 1A and the procedure below.

a) A solution of 3-methoxyphenylethylamine (0.2 mol) and formaldehyde(0.22 mol) in aqueous HCl (20%, 500 mL) was heated at 80° C. for 4hours. The reaction was then concentrated to dryness, and the residuewas dissolved in hydrobromic acid (40% aqueous, 500 mL), and refluxedfor 24 hours. The reaction was concentrated to give a brownish solid,which was used without purification. To the residue was added water (200mL) and tetrahydrofuran (“THF”) (300 mL), and to the resulting mixturewas very carefully added with sodium carbonate (solid, 0.5 mol),followed by di-tert-butyl dicarbonate (0.3 mol). After 15 hours at roomtemperature, the reaction was extracted with ethyl acetate (1 L), andthe organic extract was washed with saturated potassium dihydrophosphateand brine, dried over anhydrous magnesium sulfate and filtered.

The residue after concentration of the filtrate was dissolved indichloromethane (“DCM”; 100 mL), and to it was slowly added acetic acid(500 mL) and surfuryl chloride (0.6 mol). After the reaction mixture wasstirred at room temperature for 24 hours, the reaction was concentratedto dryness, and further dried under high vacuum for 2 hours. The crudeproduct was used without further purification for next step. The crudeproduct was dissolved in water/THF (200 mL/400 mL), and to it was addedcarefully and slowly sodium carbonate (0.5 mol) with good stirring,followed by di-tert-butyl dicarbonate (0.3 mol). After the reactionmixture was stirred for 12 hours, the reaction was carefully neutralizedwith phosphoric acid (2 M) to pH about 7. The resulting mixture wasextracted with ethyl acetate (500 mL×2), and the combined extracts werewashed with water and brine, dried over anhydrous magnesium sulfate,filtered and concentrated. The crude solid was recrystallized from ethylacetate and hexane (about 1:2 ratio) to yield a white solid. The motherliquid was concentrated and purified by column, eluting with 0-10% ethylacetate in 4:1 hexane:methylene chloride. The combined yield is 14.5 g(23% from commercial 3-methoxyphenethylamine). MS (API-ES⁺) m/z: 262,264, 266 (M+H-tert-butyl⁺).

The product obtained above was dissolved in DCM (100 mL) and pyridine(50 mL). The resulting solution was cooled to −40° C., and to it wasadded triflic anhydride (51 mmol) slowly. After the reaction mixture wasgradually warmed to room temperature over 4 hours, the reaction mixturewas partitioned between ethyl acetate (500 mL) and water (100 mL), andthe organic layer was washed with water (100 mL, twice) and brine (50mL), dried over anhydrous magnesium sulfate, filtered and concentrated.The residue was purified by column, eluting with 0-5% ethyl acetate in5:1 hexane:DCM to give the corresponding triflate (9.73 g, 48% yield).

A mixture of 10 mmol of the triflate, 1.0 mmol of1,3-diphenylphosinepropane (“dppp”) and 40 mmol ofdi-isopropylethylamine (“DIEA”) in 100 mL of dry dimethylformamide(“DMF”) and 50 mL of anhydrous CH3OH was flushed with CO for 15 min, andthen 1.0 mmol of Pd(OAc)2 was added under the atmosphere of CO.Subsequently, the resulting mixture was stirred at 70° C. overnightunder an atmosphere of CO. The solvent was removed and the residue waspurified by column chromatography using EtOAc/hexane=1/4 (v/v) as theeluent to give compound 1.1 with a 56% yield. ESI-MS (m/z): (M⁺)+Na382.1; ¹H NMR (CD3OD, 400 MHz): δ 7.32 (s, 1H), 4.60 (s, 2H), 3.95 (s,3H), 3.69 (m, 2H), 2.84 (m, 2H), 1.50 (s, 9H) ppm.

b) A mixture of 1.1 (5 mmol) and 30 mmol of LiI in 20 mL of pyridine wasreflux overnight. The solvent was removed and the residue was dissolvedin EtOAc. The resulting solution was then washed with saturated aqueousNH4Cl and dried with anhydrous Na2SO4. The solvent was removed and theresidue was dried in vacuo to give a quantitative yield of compound 1.3.The crude product was carried on the next step without furtherpurification. ESI-MS (m/z): (M-tBu+1), 290.

c) A solution of Boc-Dap-OH (10 mmol) in methanol (30 mL) was treatedwith trimethylsilyldiazomethane until the color remained light yellowfor 10 seconds. The mixture was concentrated, and the residue wasdissolved in DCM (30 mL). To the solution was added triethylamine (20mmol) and followed by 3-thienylcarboxyl chloride (11 mmol). After 0.5hour at room temperature, the reaction was filtered through silica gel,and concentrated. The residue was purified by column with 10-50% ethylacetate in hexane. The product obtained this way was dissolved in DCM(10 mL) and treated with HCl (4 M in dioxane, 10 mL). After 5 hours, thereaction was concentrated to give the title compound (60-80% overallyield).

d) A mixture of 1.2 (4 mmol), 1.3 (4.4 mmol), 5.0 mmol ofo-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium fluorophosphate(“HATU”) and 20 mmol of Et3N in 20 mL of DMF was stirred at roomtemperature overnight. The solvent was removed and the residue waspurified by column chromatography using CH₂Cl₂/EtOAc=6/4 (v/v) as eluentto give compound 1.4 with a 60% yield. ESI-MS (m/z): (M+1) 556.1.

e) A solution of 2 mmol of 1.4 in 9 mL of TFA and 3 mL of CH₂Cl₂ wasstirred at room temperature for 6 hours. The solvent was then removedand the residue was diluted with saturated aqueous NaHCO₃. The mixturewas extracted with EtOAc for 3 times. The extracts were then dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give compound 1.5 which was used without further purification.ESI-MS (m/z): (M+1) 456.1.

f) Intermediate compound 1.11 was prepared according to Scheme 1B andthe procedure below.

To a solution of 100 mmol of commercially available6-hydroxy-[2H]-benzofuran-3-one (compound 1.8) and 150 mmol of imidazolein 300 mL of dry DMF was added 110 mmol oftert-butyldimethylsilylchloride (“TBDMSCl”) at room temperature, theresulting mixture was stirred at room temperature overnight. The solventwas removed, and the residue was diluted with 100 mL of EtOAc, washedwith saturated aqueous NH₄Cl, and dried with anhydrous Na₂SO₄. Thesolvent was removed, and the residue was purified to give correspondingintermediate in 70% yield. ESI-MS (m/z): (M+H⁺) 265.1.

The intermediate is dissolved in 100 mL of CH₃OH was added 20 mmol ofNaBH₄ at room temperature. After stirring at room temperature for 12hours, the reaction mixture was treated with 10 mL of acetone.Subsequently, 60 mL of 4.0 N HCl were added to the mixture, and themixture was stirred at room temperature overnight. The organic solventwas removed, and the residue was extracted with EtOAc for several times.The extract was then washed with brine and dried with anhydrous Na₂SO₄.The solvent was removed and the residue was dissolved in 100 mmol ofEt₃N and 180 mL of dry CH₂Cl₂ was added 66 mmol of PhNTf₂ at 0° C., theresulting mixture was stirred at room temperature overnight. The solventwas removed, and the residue was purified to give compound 1.9 in 90%yield. ¹H NMR (400 MHz, CD₃Cl): δ 7.75 (d, J=1.9 Hz, 1H), 7.66 (d, J=8.5Hz, 1H), 7.50 (s, 1H), 7.21 (d, J=8.5 Hz, 1H), 6.85 (d, J=1.9 Hz, 1H)ppm.

A mixture of 50 mmol of compound 1.9, 2.5 mmol of dppp(diphenylphosphine-1,3-propane) and 2.5 mmol of Pd(OAc)₂ in 100 mmol ofDIEA, 125 mL of dry DMF, and 125 mL of anhydrous MeOH was stirred at 65°C. under an atmosphere of CO overnight. The solvent was removed and theresidue was purified by column chromatography to give compound 1.10 in65% yield. ¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 7.99 (d, J=8.3 Hz,1H), 7.78 (s, 1H), 7.65 (d, J=8.3 Hz, 1H), 6.85 (s, 1H), 3.97 (s, 3H)ppm; ESI-MS (m/z): (M+1) 177.10.

A mixture of 20 mmol of compound 1.10 and 80 mmol of LiOH.H₂O in 60 mLof THF and 15 mL of H₂O was stirred at room temperature for 1 hour,followed by adding 80 mL of 1.0N aq. HCl. The organic solvent wasremoved and the residue was diluted with 50 mL of brine. The mixture wasthen extracted with EtOAc, and the extract was dried with anhydrousNa₂SO4. The solvent was removed and the residue was dried in vacuo togive a quantitative yield of compound 1.11. ¹H NMR (400 MHz, CD₃OD): δ8.14 (s, 1H), 7.92 (m, 2H), 7.67 (d, J=8.5 Hz, 1H), 6.92 (s, 1H) ppm;ESI-MS (m/z): (M+H⁺) 163.1.

g) A mixture of 0.25 mmol of compound 1.11 and 0.26 mmol of HATU in 1mmol of DIEA and 2 mL of DMF was stirred at room temperature for 30 min,followed by adding a solution of 0.22 mmol of compound 1.5 in 1 mL ofDMF. The resulting mixture was stirred 45° C. for 12 hours. The solventwas removed, and the residue was purified to give compound 1.6 in 50-65%yield. Subsequently, compound 1.6 was hydrolyzed with LiOH (1.0 Maqueous, 0.5 mL) in THF (3 mL) for 2 hours. The reaction mixture wasthen acidified with HCl (aqueous), extracted with ethyl acetate (50 mL),dried over anhydrous magnesium sulfate and concentrated to give compound1 in quantitative yield. ¹H NMR (400 MHz, CD₃OD): δ 7.91 (s, 1H), 7.75(d, J=8.0 Hz, 1H), 7.67 (s, 3H), 7.36 (d, J=8.0 HZ, 1H), 7.13 (s, 1H),6.96 (s, 1H), 5.01 (t, J=6.8 Hz, 1H), 4.68 and 4.89 (m, 2H), 3.85 (d,J=6.8 Hz, 2H), 3.70 and 4.02 (m, 2H), 2.93 (m, 2H) ppm; ESI-MS (m/z):(M+1) 586.10.

Example 2

This example describes the synthesis of

which was prepared according to the procedure of Example 1g except that4-chlorobenzoic acid was used instead of compound 1.11. ¹H NMR (400 MHz,CD3OD): δ 7.64 (m, 2H), 7.35-7.49 (m, 5H), 7.11 (s, 1H), 4.98 (t, J=8.0Hz, 1H), 4.63 and 4.88 (m, 2H), 3.83 (d, J=8.0 Hz, 2H), 3.68 and 3.98(m, 2H), 2.89 (m, 2H) ppm; ESI-MS (m/z): (M+1) 579.90.

Example 3

This example describes the synthesis of

which was prepared according to Scheme 2 and the procedure below.

a) To a solution of 10 mmol of commercially available 3.1 in 20 mL ofMeOH and 20 mL of CH₂Cl₂ was slowly added 20 mmol of 2.0M TMSCHN₂ inhexanes at 0° C., and the resulting mixture was stirred at roomtemperature for 30 minutes. The solvent was removed and the residue wasdried in vacuo to give crude 3.2.

b) Compound 3.2 was then stirred with 15 mmol of isopropylazide in thepresence of 0.2 mmol of CuI, 0.2 mmol of Et₃N in 50 mL of CH₃CN at roomtemperature overnight. The solvent was removed and the residue waspurified by column chromatography to give compound 3.3 in 55% yield.ESI-MS (m/z): (M+1) 313.20.

c) A mixture of 2 mmol of compound 3.3 in 10 mL of 4.0 N HCl in dioxanewas stirred at room for 12 hours. The solvent was removed and theresidue was dried in vacuo to give compound 3.4 in quantitative yield.ESI-MS (m/z): (M+1) 213.10.

d) A solution of 1.1 (3.60 g, 10 mmol) in DCM (20 mL) was treated withHCl in 1,4-dioxane (4.0 M, 10 mL) at room temperature. After 2 hours,the reaction was concentrated to give compound 3.5 in quantitativeyield.

e) Example 3.5 (10 mmol) was mixed with EDC (2.11 g, 11 mmol),N,N-dimethylaminopyridine (“DMAP”, 0.1 g), triethylamine (2.02 g) andExample 1.11 (1.62 g, 10 mmol) in anhydrous DMF (50 mL). After 15 hoursat room temperature, the reaction mixture was diluted with ethyl acetate(200 mL), washed with water (30 mL, 3 times), dried with anhydrousmagnesium sulfate and filtered. The residue after concentration of thefiltrate was purified by column eluting with 10-30% ethyl acetate inhexane to give the title compound (3.7 g, 92%): ESI-MS (m/z): (M+1)213.1.

f) Compound 3.7 was made according to Example 1b except that compound3.6 was used instead of compound 1.1.

g) A mixture of 0.25 mmol of compound 3.7 and 0.26 mmol of HATU in 1mmol of DIEA and 2 mL of DMF was stirred at room temperature for 30minutes, followed by adding a solution of 0.22 mmol of compound 3.4 in 1mL of DMF. The resulting mixture was stirred 45° C. for 4 hours. Thesolvent was removed, and the residue was purified to give intermediateester, which was subsequently treated with LiOH in THF and water to givethe desired compound 3 in quantitative yield. ¹H NMR (400 MHz, CD₃OD) δ7.90 (s, 2H), 7.74 (m, 1H), 7.64 (s, 1H), 7.34 (m, 1H), 6.93 (s, 1H),5.03 (m, 1H), 4.82 (m, 1H), 4.65 and 4.88 (m, 2H), 3.72 and 3.97 (m,2H), 3.40 (m, 1H), 3.18 (m, 1H), 2.90 (m, 2H), 1.55 (m, 6H) ppm; ESI-MS(m/z): (M+1) 570.1.

Example 4

This example describes the synthesis of

which was prepared according to Scheme 3 and the procedure below.

a) Boc-DAP-OH (0.2 g, 1.0 mmol), 2,4-dichloropyrimidine (0.29 g, 2.0mmol), and diisopropylethylamine (0.51 mL, 2.9 mmol) in ethanol (5 mL)were heated to 75° C. for 14 hours. The reaction mixture was cooled toroom temperature and the solvent removed under reduced pressure. Theresulting crude product 4.1 was pure enough to carry forward to the nextchemical transformation.

b) Crude residue 4.1 (0.31 g, 1.0 mmol) was dissolved in 9:1benzene:methanol (5 mL). Trimethylsilyldiazomethane (1.0 mL, 2.0M inhexanes) was added slowly to the stirring reaction mixture and stirredfor an additional 1 hour. The solvents were removed under reducedpressure to obtain oily crude residue. Purification by silica gel columnchromatography using 50% ethyl acetate in hexanes was performed toafford pure 4.2 (0.21 g, 65%).

c) Compound 4.2 (0.21 g, 0.6 mmol) was dissolved in dichloromethane (5mL). Trifluoroacetic acid (2.5 mL) was added and the reaction wasstirred for 1 hour. The resulting reaction mixture was concentrated toremove any excess trifluoroacetic acid to afford amine 4.3 inquantitative yield.

d) Compound 4.4 was made according to Example 3d-f except that4-chlorobenzoic acid was used instead of compound 1.11.

e) Compound 4 was made according to Example 3g except that compound 4.4was used instead of compound 3.7 and compound 4.3 was used instead ofcompound 3.4.

Example 5

This example describes the synthesis of

which was prepared according to Scheme 4 and the procedure below.

a) To a solution of methane sulfonamide (1.01 g, 10.7 mmol) in 15 mL DMFwas added 20 M aqueous NaOH (0.68 mL, 13.6 mmol), resulting in a whiteprecipitate. The solution was cooled to 0° C., carbon disulfide (0.4 mL,6.63 mmol) slowly added, and stirred at 0° C. for 15 minutes. Additional20M aqueous NaOH (0.32 mL, 6.4 mmol) and carbon disulfide (0.2 mL, 3.31mmol) were added and the reaction stirred at 0° C. for 20 minutes, thenraised to room temperature. At 30 minutes all precipitate had returnedto solution, and the reaction mixture was cooled to 0° C. Methyl iodide(1.33 mL, 21.364 mmol) was added and the reaction stirred at 0° C. for20 minutes and at room temperature for 1.5 hours. 20 mL water was addedto the reaction and extracted five times with ethyl acetate. Thecombined organic extracts were dried over MgSO₄ and concentrated todryness. Recrystallization from hot ethyl acetate and hexanes afforded1.44 g compound 5.1. ESI-MS (m/z): (M+H⁺) 200.0.

b) To a solution of Boc-Dap-OH (109 mg, 0.53 mmol) and compound 5.1(125.7 mg, 0.632 mmol) in 5 mL ethanol was added 1.0M aqueous NaOH (0.8mL, 0.8 mmol). The reaction was stirred until conversion was complete,and then concentrated to dryness. The residue was dissolved in water andwashed three times with ether. The aqueous layer was acidified to pH 1with 2.0M phosphoric acid, and extracted four times with ethyl acetate.The combined ethyl acetate extracts were dried over MgSO₄ andconcentrated to dryness to afford 160.4 mg of compound 5.2. ESI-MS(m/z): (M+Na⁺) 378.0.

c) To a solution of compound 5.2 (160.4 mg, 0.452 mmol) in 1:1dichloromethane:methanol was added trimethylsilyldiazomethane as a 2.0 Msolution in ether (0.4 mL, 0.8 mmol). The reaction was stirred at roomtemperature until conversion to the methyl ester was complete, and thenconcentrated to dryness. The product was purified via flashchromatography to afford 146.6 mg of compound 5.3. ESI-MS (m/z): (M+Na⁺)270.0; ¹H NMR (400 MHz, chloroform-d) δ 1.46 (s, 9H), 2.42 (s, 3H), 3.02(s, 3H), 3.63 (m, 1H), 3.75 (m, 1H), 3.82 (s, 3H), 4.51 (m, 1H).

d) To a solution of compound 5.3 (146.6 mg, 0.40 mmol) in 2 mL methanolwas added ammonia, 7N in methanol (0.6 mL, 4.2 mmol). This mixture wascooled to 0° C., and a solution of silver nitrate (75.5 mg, 0.444 mmol)in 0.4 mL acetonitrile was dropwise added. The reaction was stirred andallowed to reach room temperature. At three hours solvent was removed,the residue suspended in ethyl acetate, and filtered through celite. Thefiltrate was concentrated to dryness and redissolved in dichloromethane,to which was added HCl, 4.0 M in dioxane (0.5 mL, 2.0 mmol). Thissolution was stirred at room temperature for 8 hours and concentrated todryness to afford compound 5.4 as an HCl salt. ESI-MS (m/z): (M+H⁺) 239.

e) Compound 5 was made according to Example 3g except that compound 4.1was used instead of 3.7 and compound 5.4 was used instead of compound3.4. ESI-MS (m/z): (M+H⁺) 590.0.

Example 6

This example describes the synthesis of

which was prepared according to Scheme 5 and the procedure below.

a) A solution of (L)-Boc-Dap-OH (10 mmol), dimethylN-cyanodithioimniocarbonate (10 mmol) and DIEA (30 mmol) in ethanol wasstirred at room temperature for 1 hour. Then, pyrrolidine (20 mmol) wasadded, and the reaction was heated at 65° C. for 10 hours. The reactionmixture was then diluted with ethyl acetate (150 mL), and was extractedwith saturated NaH₂PO₄ (50 mL, the aqueous layer pH is between 4-6),water (50 ml) and brine. The organic layer was dried with anhydrousmagnesium sulfate, filtered and concentrated. The crude product wasdissolved in 4:1 DCM:MeOH, cooled at 0° C. and to it was addedtrimthylsilyldiazomethane until it stays yellow for 30 seconds. Thesolution is concentrated and the residue was purified by column with30-100% ethyl acetate in hexane to give the title compound in 20-30%yield. MS (m/z): 240 (M-99).

b) Compound 6.1 (72 mg, 0.20 mmol) in DCM (1 mL) was treated with HCl (4M in dioxane) for 2 hours. The reaction mixture was concentrated to givecompound 6.2.

c) Compound 6 was made according to Example 3g except that compound 6.2was used instead of compound 3.4. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s,1H), 7.63 (m, 3H), 7.37 (d, 1H), 6.85 (s, 1H), 6.32 (d, 1 H), 4.68 (s,2H), 4.31 (m, 1H), 3.85 (m, 2H), 3.60 (m, 4H), 2.88 (m, 2H), 1.89 (m,4H) ppm; ESI-MS (m/z): (M+1) 597.1.

Example 7

This example describes the synthesis of

which was prepared according to Scheme 6 and the procedure below.

a) To a solution of H-2-Mercapto-His-OH (598.8 mg, 3.2 mmol) in 5 mLmethanol was added 0.26 mL sulfuric acid. This mixture was stirred atroom temperature for 18 hours. Additional sulfuric acid (0.1 mL, 0.6mmol) was added and the reaction stirred at 50° C. for 4.5 hours. Sodiumcarbonate (850.3 mg, 8.02 mmol) was slowly added, and the reactionconcentrated via rotary evaporation to remove most of the methanol. 6 mLTHF and 3 mL water were added with sodium carbonate (0.851 g, 8.03 mmol)and Boc₂O (696.5 mg, 3.19 mmol). The reaction was stirred at roomtemperature for 1 hour, diluted with ethyl acetate, and washed withwater and brine. The organic layer was dried over MgSO₄ and concentratedto dryness. Purification via flash chromatography afforded 283.5 mg ofcompound 7.1. ESI-MS (m/z): (M+H⁺) 316.1.

b) Compound 7.1 (283.5 mg, 0.90 mmol) and 3-chloroperoxybenzoic acid(568.4 mg, 2.53 mmol) were dissolved in 6 mL dichloromethane and stirredat room temperature for 1.5 hours. The reaction was diluted withdichloromethane and poured into 1.0 M potassium carbonate. The aqueouslayer was adjusted to neutral pH with 2.0 M phosphoric acid andextracted three times with dichloromethane. The combined organicextracts were dried over MgSO₄ and concentrated to dryness. Purificationvia flash chromatography afforded 240.8 mg of compound 7.2. ESI-MS(m/z): 370.1 (M+Na⁺), 248.1 (M-Boc+H⁺); ¹H NMR (400 MHz, CDCl₃) δ 1.43(s, 9H), 3.14 (m, 2H), 3.26 (s, 3H), 3.74 (s, 3H), 4.61 (m, 1H), 7.02(s, 1H).

c) To a solution of compound 7.2 (240.8 mg, 0.6931 mmol) indichloromethane was added HCl, 4.0 M in dioxane (1.0 mL, 4.0 mmol). Thereaction was stirred at room temperature for 1.5 hours and thenconcentrated to dryness to afford compound 7.3 as an HCl salt. ESI-MS(m/z): (M+H⁺) 248.

d) Compound 7 was made according to Example 3g except that compound 4.1was used instead of compound 3.7 and compound 7.3 was used instead ofcompound 3.4. ESI-MS (m/z): (M+H⁺) 599.0; ¹H NMR (400 MHz, CDCl₃) δ 2.88(s, 2H), 3.10 (m, 1H), 3.21 (s, 3H), 3.34 (m, 1H), 3.67 (1H), 3.97 (1H),4.63 (1H), 4.85 (1H), 5.04 (dd, 1H), 7.19 (s, 1H), 7.49 (m, 5H).

Example 8

This example describes the synthesis of

which was prepared in according to Scheme 7A and the procedure below.

a) A three-neck flask containing 32 mmol of LiCl was flamed with a gaslamp in vacuo, followed by flushing with N₂. This sequence was repeatedfor 3 times in order to get dry LiCl. To the flask was added 10 mmol of(R,R)-(−)-pseudoephedrine glycinamide hydrate (A. G. Myers et al J. Org.Chem. 64: 3322-3327 (1999)) and 30 mL of dry THF at room temperatureunder an atmosphere of N₂. The suspension was then treated with 31 mmolof LiHMDS (1.0 M in THF) at 0° C. with stirring for 1 hour, followed byadding a solution of 10 mmol of 3-methylthiobenzyl chloride (S. Lauferet al J. Med. Chem. 45: 2733-2740 (2002)) in 5 mL of dry THF. Theresulting mixture was stirred at 0° C. overnight and quenched by adding10 mL of water. The solvent was removed, and the residue was dilutedwith 50 mL of water. The mixture was extracted with CH₂Cl₂ for 3 times.The organic extract was combined and dried with anhydrous Na₂SO₄.Subsequently, the solvent was removed, and the residue was purified togive the desired alkylated intermediate in 70% yield. ESI-MS (m/z):(M+H⁺) 359.2.

A mixture of 5 mmol of the alkylated intermediate in 12 mL of 1.0 N NaOHwas refluxed until the starting material was consumed. The mixture wasdiluted with 20 mL, of water and extracted with CH₂Cl₂ for 3 times. Theaqueous phase was then stirred with 6 mmol of (Boc)₂O and 12 mmol ofNaHCO₃ in 30 mL of 1,4-dioxane for 15 hours. The organic solvent wasremoved, and the residue was diluted with 30 mL of water and extractedwith CH₂Cl₂. The aqueous phase was subsequently treated with solidcitric acid to adjust the pH value to 4.0, flowed by extracting withEtOAc for 3 times. The organic extract was dried with anhydrous Na₂SO₄.The solvent was removed, and the residue was dried in vacuo to givecompound 8.2 in quantitative yield. ESI-MS (m/z): (M+H⁺) 334.10.

b) A mixture of 5 mmol of compound 8.2 in 10 mL of CH₃OH and 10 mL ofCH₂Cl₂ was added 10 mmol of (trimethylsilyl)diazomethane (2.0 M inhexanes) at 0° C., the resulting mixture was stirred at room temperaturefor 30 minutes. The solvent was removed, and the residue was dried invacuo to give the desired ester in quantitative yield. ESI-MS (m/z):(M+H⁺) 348.10.

To a solution of the ester in 20 mL of CH₃OH and 2 mL of water was added12 mmol of Oxone® at room temperature, and the resulting suspension wasstirred at room temperature for 15 hours. The reaction mixture wasconcentrated and diluted with 50 mL of EtOAc, washed with water, anddried with anhydrous Na₂SO₄. The solvent was removed and the residue wasdried in vacuo to give compound 8.3 in quantitative yield. ¹H NMR (400MHz, CD₃Cl): δ 7.82 (m, 1H), 7.69 (s, 1H), 7.50 (m, 1H), 7.43 (m, 1H),5.03 (m, 1H), 4.62 (m, 1H), 3.74 (s, 3H), 3.26 (m, 1H), 3.09 (m, 1H),3.03 (s, 3H), 1.39 (s, 9H) ppm; ESI-MS (m/z): (M-tBoc+H⁺) 258.1.

c) A mixture of 2 mmol of compound 8.3 in 10 mL of 4.0 N HCl in dioxanewas stirred at room temperature for 15 hours. The solvent was removed,and the residue was dried in vacuo to give compound 8.4 in quantitativeyield as an HCl salt. ¹H NMR (400 MHz, CD₃OD): δ 7.95 (m, 1H), 7.87 (s,1H), 7.64 (m, 2H), 4.44 (t, J=6.85 Hz, 1H), 3.82 (s, 3H), 3.41 (m, 1H),3.29 (m, 1H), 3.13 (s, 3H) ppm; ESI-MS (m/z): (M+H⁺) 258.10.

d) Compound 8 was made according to Example 3g except that compound 4.1was used instead of compound 3.7 and compound 8.4 was used instead ofcompound 3.4. ¹H NMR (400 MHz, CD₃OD): δ 7.92 (s, 1H), 7.81 (d, J=7.92Hz, 1H), 7.68 (d, J=7.83 Hz), 7.56 (t, J=7.83 Hz, 1H), 7.30-7.49 (m,5H), 5.06 (m, 1H), 4.60 and 4.83 (m, 2H), 3.95 and 3.66 (m, 2H), 3.44(d, J=13.44 Hz, 1H), 3.14 (m, 1H), 3.08 (s, 3H), 2.85 (m, 2H) ppm;ESI-MS (m/z): (M+H⁺) 609.05.

e) Compound 8.4 can also be prepared according to Scheme 7B and theprocedure below.

A mixture of 8.5 (1.0 mmoL), methyl iodide (1.2 mmoL) and potassiumcarbonate (2 mmoL) in 20 mL of acetone was heated at 50° C. for 3 hours.The solvent of the reaction mixture was removed under reduced pressure.The residue was partitioned between EtOAc and water. The aqueoussolution was extracted with EtOAc, and combined organic solution waswashed with brine, dried over Na₂SO₄, filtered, concentrated. The crudeproduct as a white solid (yield 98%) was used for next step withoutpurification.

To a solution of the compound (1 mmol.) made above in 4 mL of THF at 0°C. was added LiAlH₄ (1.1 mmoL) slowly. The reaction mixture was allowedto warm to room temperature and stirred for 1 hour. The reaction wasadded consecutively with water, 15% aqueous NaOH and water with strongstirring. The filtration and evaporation of filtrate provided the crudeproduct 8.6 (yield 92%). No purification was needed. ¹H NMR (400 MHz,CDCl₃) δ 3.05 (s, 3H), 4.75 (s, 2H), 7.53 (t, J=7.58 Hz, 1H), 7.62 (d,J=7.34 Hz, 1H), 7.81 (d, J=7.83 Hz, 1H), 7.93 (s, 1H).

Solid tetrapropylammonium perruthenate (“TPAP”, 0.05 mmol) was added inone portion to a stirred mixture of compound 8.6 (1 mmol.),4-methylmorpholine N-oxide (“NMO”; 1.5 mmol.) and powdered 4A molecularsieve (equal weight to that of NMO) in 5 mL of DCM at room temperatureunder N₂. The reaction mixture was stirred at room temperature. for 1hour, and then filtered through a short pad of silica gel, eluting withmixture of DCM and AcOEt (1:1). The filtrate was concentrated and theresidue was purified with chromatography (SiO2, AcOEt/hexane 2:1) toafford compound 8.7 (yield 72%). ¹H NMR (400 MHz, CDCl₃) δ 3.14 (s, 3H),7.81 (t, J=7.58 Hz, 1H), 8.21 (t, J=9.05 Hz, 2H), 8.46 (s, 1H), 10.12(s, 1H) ppm.

The N, N, N′, N′,-tetramethylguanidine (“TMG”; 1.05 mmole) was addedslowly to a solution of (d,1)-Cbz-α-phosphonoglycine trimethylester (1.1mmole) in 4 ml of DCM at room temperature. After 15 minutes, the mixturewas cooled to −30° C. and compound 8.7 (1 mmole) added dropwise. Themixture was kept at −30° C. for 20 minutes and slowly allowed to warm to0° C. The solution was diluted with AcOEt and washed consecutively with1 N NaHSO₄ and brine. The solution was dried (Na₂SO₄), and solventevaporated to provide crude product. Purification of the crude producton chromatography (SiO2, AcOEt/hexanes/DCM 3:3:1) to give product 8.8(yield 72%). ¹H NMR (400 MHz, CDCl₃) δ 2.97 (s, 3H), 3.86 (s, 3H), 5.08(s, 2H), 6.78 (s, 1H), 7.34 (d, J=6.36 Hz, 5H), 7.50 (t, J=7.83 Hz, 1H),7.72 (d, J=7.34 Hz, 1H), 7.85 (d, J=7.34 Hz, 1H), 8.04 (s, 1H). Olefinicproton in the minor trans isomer at 7.19 ppm (s, 1H). ESI-MS (m/z):(M+H⁺) 346.

To the solution of 8.8 (1 mmole) in MeOH (20 mL, presparged withnitrogen gas) in a glass pressure vessel was added chiral catalyst(+)-bis((2S,5S)-2,5-dimethylphospholano)benzene(cyclooctadiene)rhodium(I)tetrafluoroborate(0.01 mmole). The reactor was then pressurized with H₂ to 40 psi andshaking was continued at room temperature for 17 hours. The solvent wasevaporated. The residue was dissolved in AcOEt and filtered through aplug of SiO₂ with AcOEt. The filtrate was evaporated to provide thecrude product 8.9. (yield, 72%). ¹H NMR (400 MHz, CDCl₃) δ 2.98 (s, 3H),3.13 (dd, J=13.69, 6.36 Hz, 1H), 3.29 (m, 1H), 3.76 (s, 3H), 4.69 (m,1H), 5.06 (m, 2H), 5.44 (d, J=6.85 Hz, 1H), 7.31 (m, 5H), 7.41 (d,J=7.34 Hz, 1H, 7.47 (t, J=7.83 Hz, 1H), 7.72 (s, 1H), 7.82 (d, J=7.34Hz, 1H). ESI-MS (m/z): (M+H⁺) 348.

The compound 8.9 was hydrogenated (Pd/C, MeOH,) with a hydrogen balloonto afford compound 8.4 (yield 98%). ESI-MS (m/z): (M+H⁺) 258.

Example 9

This example describes the synthesis of

which was prepared in according to Scheme 8 and the procedure below.

a) Compound 9.1 was made according to Example 1d-e except that compound8.4 was used instead of compound 1.3.

b) Compound 9 was made according to Example 3g except that compound 9.1was used instead of compound 3.7 and 2-hydroxycinnamic acid was usedinstead of compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 7.92 (m, 2H), 7.81(m, 1H), 7.68 (s, 1H), 7.58 (m, 2H), 7.28 (m, 2H), 7.18 (m, 1H), 6.84(m, 2H), 5.07 (m, 1 H), 4.80 and 4.88 (m, 2H), 3.96 (m, 2H), 3.42 (m,1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.71-2.91 (m, 2H) ppm; ESI-MS (m/z):(M+H⁺) 617.10.

Example 10

This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 wasused instead of compound 3.7 and 2-fluorocinnamic acid was used insteadof compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.81 (m, 3H),7.68 (m, 1H), 7.57 (m, 1H), 7.42 (m, 1H), 7.29 (m, 2H), 7.23 (m, 1H),7.16 (m, 1H), 5.06 (m, 1H), 4.81 and 4.88 (m, 2H), 3.82 and 3.97 (m,2H), 3.44 (m, 1H), 3.16 (m, 1H), 3.08 (s, 3H), 2.86 and 2.93 (m, 2H)ppm; ESI-MS (m/z): (M+H⁺) 619.10.

Example 11

This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 wasused instead of compound 3.7 and 6-indazolecarboxylic acid was usedinstead of compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 8.13 (s, 1H), 7.93(m, 3H), 7.83 (m, 1H), 7.70 (m, 1H), 7.60 (m, 1H), 7.20 and 7.34 (m,1H), 5.06 (m, 1H), 4.64 and 4.88 (m, 2H), 3.69 and 3.98 (m, 2H), 3.40(m, 1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.88 (m, 2H) ppm; ESI-MS (m/z):(M+H⁺) 615.15.

Example 12

This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 wasused instead of compound 3.7 and 2-indolecarboxylic acid was usedinstead of compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 7.93 (s, 1H), 7.83(m, 2H), 7.72 (m, 1H), 7.83 (m, 1H), 7.57 (m, 1H), 7.45 (m, 1H), 7.27(s, 1H), 7.20 (m, 1H), 7.07 (m, 1H), 6.93 (s, 1H), 5.08 (m, 1H), 4.88(m, 2H), 4.07 (m, 2H), 3.46 (m, 1H), 3.15 (m, 1H), 3.08 (s, 3H), 2.96(m, 2H) ppm; ESI-MS (m/z): (M+H⁺) 614.10.

Example 13

This example describes the synthesis of

which was prepared according to Example 3g except that compound 9.1 wasused instead of compound 3.7 and 2-quinolinecarboxylic acid was usedinstead of compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 8.51 (m, 1H), 8.08(m, 1H), 8.01 (m, 1H), 7.94 (m, 1H), 7.84 (m, 2H), 7.70 (m, 3H), 7.58(m, 1H), 7.36 and 7.04 (m, 1H), 5.07 (m, 1H), 4.78 and 4.95 (m, 2H),3.79 and 4.08 (m, 2H), 3.45 (m, 1H), 3.17 (m, 1H), 3.09 (s, 3H), 2.97(m, 2H) ppm; ESI-MS (m/z): (M+H⁺) 626.10.

Example 14

This example describes the synthesis of

which was prepared according to Scheme 9 and the procedure below.

a) To a solution of 3-carboxylbenzenesulfonyl chloride (3.54 g, 16 mmol)in ethyl acetate (50 mL) at 0° C. was added concentrated ammonia (2.5mL). The reaction was neutralized with HCl in dioance (20 mL), dilutedwith ethyl acetate (100 mL), dried with anhydrous sodium sulfate andfiltered. Concentration of the filtrate yielded the title compound,which was used without purification.

b) Crude compound 14.1 was dissolved in THF (50 mL), to it was addedborane (1.0 M in THF, 50 mL) over 20 minute period. After the reactionwas stirred at room temperature for 15 hours, the reaction was dilutedwith brine (20 mL) and water (10 mL), extracted with ethyl acetate (100mL). The organic extract was dried over anhydrous sodium sulfate andfiltered. Concentration of the filtrate yielded the title compound,which was used without further purification.

c) To crude compound 14.2 solution in DCM (100 mL) was added activated4A molecular sieve powder (8 g), pyridinium dichromate (7.55 g, 20mmol). After the reaction was stirred at room temperature for 2 hours,the reaction mixture was filtered through silica gel (50 g), rinsed withethyl acetate. The residue after concentration of the filtrate waspurified by silica gel column with 30-50% ethyl acetate in hexane togive compound 14.3 (477 mg, 16%, 3 steps). ESI-MS (m/z): (M+H⁺) 186.

d) Compound 14.4 was made according to Example 8e except that compound14.3 was used instead of compound 8.7. MS (ESI⁺) m/z: 260 (M+H⁺).

e) Compound 14 was made according to Example 3g except that compound14.4 was used instead of compound 3.4. ¹H NMR (400 MHz, CD₃OD) δ 7.89(s, 1H), 7.80 (s, 1H), 7.75 (m, 2H), 7.64 (s, 1H), 7.57 (d, 1H), 7.34(d, 2H), 6.93 9s, 1H), 5.00 (m, 1H), 3.99 (m, 1H), 3.73 (m, 1H), 3.40(dd, 1H), 3.12 (dd, 1H), 2.89 (m, 2H) ppm; ESI-MS (m/z): 616 (M+H⁺).

Example 15

This example describes the synthesis of

which was prepared according to Scheme 10 and the procedure below.

a) To a solution of 0.2 mol of furan in 200 mL of dry THF was added 0.2mol of n-BuLi (1.6 M in hexanes) at −78° C., the resulting solution wasstirred at room temperature for 4 hours. Subsequently, the mixture wascooled to −78° C. and treated with 0.21 mol of dimethyl disulfide, andthe mixture was stirred at room temperature overnight, followed byadding 10 mL of saturated aqueous NH₄Cl. The mixture was concentrated atroom temperature, and the residue was diluted with 200 mL of saturatedaqueous NH₄Cl and extracted with ether. The extract was then washed withbrine and dried with anhydrous Na₂SO₄. The solvent was removed, and theresidue was distilled to collect the fraction at 135-140° C./760 mmHg togive compound 15.1 in 55% yield. ¹H NMR (400 MHz, CD₃Cl): δ 7.50 (s,1H), 6.45 (m, 1H), 6.39 (s, 1H), 2.42 (s, 3H) ppm.

b) To a solution of 0.1 mol of compound 15.1 in 100 mL of dry THF wasadded 0.1 mol of n-BuLi (1.6 M in hexanes) at −78° C., the resultingsolution was stirred at room temperature for 4 hours. Subsequently, themixture was cooled to −78° C. and treated with 0.12 mol of dry DMF, andthe mixture was stirred at room temperature overnight. The reaction wasquenched by adding 10 mL of saturated aqueous NH₄Cl, and the mixture wasconcentrated. The residue was diluted with 100 mL of brine and extractedwith EtOAC. The extract was washed with brine and dried with anhydrousNa₂SO₄. The solvent was removed and the residue was purified to give thetitle compound in 65% yield. ¹H NMR (400 MHz, CD₃Cl): δ 9.52 (s, 1H),7.24 (d, J=3.4 Hz, 1H), 6.42 (d, J=3.4 Hz, 1H), 2.60 (s, 3H) ppm; ESI-MS(m/z): (M+H⁺) 143.1.

c) A mixture of 50 mmol of compound 15.2 and 120 mmol of m-CPBA in 100mL of CH₂Cl₂ was stirred at room temperature overnight. The mixture wasdiluted with 150 mL of CH₂Cl₂, and the mixture was washed with saturatedaqueous NaHCO₃ for several times. The solution was then dried withanhydrous Na₂SO₄ and concentrated. The residue was purified to givecompound 15.3 in 70% yield. ¹H NMR (400 MHz, CD₃Cl): δ 9.83 (s, 1H),7.33 (m, 2H), 3.27 (s, 3H) ppm; ESI-MS (m/z): (M+H⁺) 175.0.

d) Compound 15.4 was made according to Example 8e except that compound15.3 was used instead of 8.7. ESI-MS (m/z): (M+H⁺) 248.1.

e) Compound 15 was made according to Example except that compound 15.4was used instead of 3.4. ¹H NMR (400 MHz, CD₃OD): δ 7.92 (s, 1H), 7.76(m, 1H), 7.67 (s, 1H), 7.34 (m, 1H), 7.13 (s, 1H), 6.69 (s, 1H), 6.49(s, 1H), 5.11 (m, 1H), 4.73 and 4.88 (m, 2H), 3.76 and 4.02 (m, 2H),3.46 (m, 1H), 3.30 (m, 1H), 3.17 (s, 3H), 2.94 (m, 2H) ppm; ESI-MS(m/z): (M+H⁺) 605.05.

Example 16

This example describes the synthesis of

which was prepared according to the procedure below.

To a solution of 0.2 mmol of compound 8.4 (Example 8c or 8e) in 1 mmolof Et₃N and 5 mL of dry CH₂Cl₂ was added 0.22 mmol of2,6-dichlorobenzoyl chloride at 0° C., the resulting mixture was stirredat room temperature for 12 hours. The solvent was removed and theresidue was dried in vacuo. Subsequently, the residue was treated with0.8 mmol of LiOH.H₂O in 2 mL of THF and 0.5 mL of H₂O. After stirring atroom temperature for 30 minutes, the reaction mixture was added 1.0 mLof 1.0N aq. HCl. The organic solvent was removed, and the residue wasdiluted with 10 mL of brine. The mixture was extracted with EtOAc andthe extract was dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was dried in vacuo to give the desired compound in 65%yield. ¹H NMR (400 MHz, CD₃OD) δ 7.92 (s, 1H), 7.82 (d, J=6.85 Hz, 1H),7.71 (d, J=6.85 Hz, 1H), 7.56 (t, J=7.83 Hz, 1H), 7.34 (m, 3H), 5.08(dd, J=9.78, 4.89 Hz, 1H), 3.45 (dd, J=14.67, 4.89 Hz, 1 H), 3.14 (dd,J=14.67, 9.78 Hz, 1H), 3.08 (s, 3H) ppm; ESI-MS (m/z): (M+H⁺) 416.00.

Example 17

This example describes the synthesis of

which was prepared according to the procedure basis.

Compound 6.1 (Example 6a, 0.2 mmol) in DCM (1 mL) was treated with HClin dioxane (4.0 M, 1 mL). After 1 hour, the solvent was evaporated. Theresidue and 1 mmol of Et₃N and 5 mL of dry CH₂Cl₂ was added 0.22 mmol of2,6-dichlorobenzoyl chloride at 0° C., the resulting mixture was stirredat room temperature for 15 hours. The solvent was removed and theresidue was dried in vacuo. Subsequently, the residue was treated with0.8 mmol of LiOH.H₂O in 2 mL of THF and 0.5 mL of H₂O. After stirring atroom temperature for 30 minutes, the reaction mixture was added 1.0 mLof 1.0 N aqueous HCl. The organic solvent was removed, and the residuewas diluted with 10 mL of brine. The mixture was extracted with EtOAcand the extract was dried with anhydrous Na₂SO₄. The solvent was removedand the residue was dried in vacuo to give the desired compound.

Example 18

This example describes the synthesis of

which is prepared according to Scheme 11 and the procedure below.

a) 1 equivalent of LiAlH₄ (1.0M in THF) was added to a 0° C. solution of1 equivalent of compound ethyl 6-indazolecarboxylate (Batt, D. G., J.Med. Chem. 43: 41-58 (2000)) at −78° C. The reaction was stirred at −78°C. for another 30 minutes, and then warmed to 0° C. An aqueous solutionof 1 equivalent of 1M NaOH was added slowly. The resulting slurry wasfiltered thru a plug of Celite and washed with a copious amount of ethylacetate. The combined organics were dried with MgSO₄ and concentrated invacuo to provide the alcohol 18.1 in high enough purity to be usedwithout further purification.

b) 1.1 equivalent of Dess-Martin periodinane was added to 1 equivalentof 18.1 in dichloromethane. After stirring the reaction for 3 hours atroom temperature, the resulting precipitate was removed by filteringthru a plug of celite. The celite plug was washed with dichloromethane.The combined organics were concentrated to provide the aldehyde 18.2 inhigh enough purity to be used without further purification.

c) 2.1 equivalents of ethyl magnesium bromide (0.5M in THF) were addedto a pre-cooled solution containing 18.2 in THF at 0° C. After 30minutes, the reaction was warmed to room temperature and stirred for anadditional 2 hours. The resulting reaction mixture was diluted withethyl acetate and washed with water. The organic layer was then driedwith MgSO₄, filtered, and concentrated in vacuo. The residue was thenpurified on silica gel column chromatography (gradient elution usingethyl acetate and hexanes) to provide pure compound 18.3.

d) To a mixture of 4-amino-2,6-dichlorophenol (1 equivalent) in 3:2THF/H₂O was added NaHCO₃ (1.1 equivalent) and Boc₂O (1.1 equivalent),after stirring overnight, the reaction was extracted with ether, anddried with MgSO₄, filtered, and concentrated in vacuo. The residue 18.4was used without purification.

e) To a solution of phenol 18.4 (1 equivalent) and 2,6-lutidine (2.2equivalent) in DCM at −78° C. was added triflic anhydride (1.2equivalent). After the reaction mixture was gradually warmed to roomtemperature overnight, the reaction mixture was diluted with ether,washed with water, dried with MgSO₄, filtered, and concentrated invacuo. The residue was then purified on silica gel column (gradientelution using ethyl acetate and hexanes) to provide pure compound 18.5.

f) A mixture of 10 mmol of the triflate 18.5, 1.0 mmol of dppp and 40mmol of DIEA (in 100 mL of dry DMF and 50 mL of anhydrous CH₃OH wasflushed with CO for 15 minutes, and then 1.0 mmol of Pd(OAc)₂ was addedunder the atmosphere of CO. Subsequently, the resulting mixture wasstirred at 70° C. overnight under an atmosphere of CO. The solvent wasremoved and the residue was purified by column chromatography with10-30% EtOAc in hexane to give compound 18.6.

g) 1 equivalent of Boc-aniline 18.6 was dissolved carefully in 6 Maqueous H₂SO₄, and the mixture was then cooled to 0° C. To it was addedslowly with vigorous stirring sodium nitrite (1.1 equivalent in water),followed by sodium iodide (5 equivalent) in 1.5 hours. After thereaction was stirred at room temperature for overnight, the reaction wasdiluted with ether, washed with water, dried with MgSO₄, filtered, andconcentrated in vacuo. The residue was then purified on silica gelcolumn (gradient elution using ethyl acetate and hexanes) to providepure compound 18.7.

h) 1 equivalent of iodide 18.7, 1 equivalent of alkyne 18.3, 0.05equivalent of CuI, and 5 equivalents of triethylamine were dissolved inbenzene and the solution degassed by bubbling N₂ thru a syringe needleand into the solution for 15 minutes. 0.05 equivalent of PdCl₂(dppf).DCM was added. After 4 hours, the reaction was diluted with ethylacetate and washed with water, brine. The organic layer was then driedwith MgSO₄, filtered, and concentrated in vacuo. The residue was thenpurified on silica gel column chromatography (gradient elution usingethyl acetate and hexanes) to provide pure compound 18.8.

i) 1 equivalent of 18.8 was dissolved in MeOH and 5% Rh/Al₂O₃ (20 weight%) was added. Under reduced pressure, oxygen was removed from the flask.The internal pressure was restored by the addition of hydrogen gasdelivered using a hydrogen filled balloon. The reaction was stirredunder an atmosphere of hydrogen gas for 14 hours. The reaction wasfiltered thru a pad of celite and concentrated in vacuo. The residue wasthen purified on silica gel column chromatography (gradient elutionusing ethyl acetate and hexanes) to provide pure compound 18.9.

j) 4 equivalents of LiI was added to 1 equivalent of compound 18.9 inpyridine. The reaction was refluxed for 14 hours, then allowed to coolto room temperature. The reaction was concentrated and the resultingresidue was partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried over MgSO₄, filtered, and concentrated. The residue was thenpurified on silica gel column chromatography (gradient elution usingethyl acetate and methanol) to provide pure compound 18.10.

k) 1 equivalent of compound 18.10, 1 equivalent of compound 8.4 (Example8c or 8e), and 3 equivalents of DIEA were dissolved in DMF. 1.1equivalent of HATU was added. The reaction was stirred at roomtemperature for 14 hours. The reaction mixture was diluted with ethylacetate and washed with water, brine. The combined organics were driedwith MgSO₄, filtered, and concentrated. The residue was then purified onsilica gel column chromatography (gradient elution using ethyl acetateand hexanes) to provide pure intermediate ester. The ester was dissolvedin methanol followed by addition of 2 equivalents of 1M LiOH(aq). Uponcompletion, the excess solvents were removed under reduced pressure andthe resulting acid was then purified by reverse phase HPLC to give purecompound 18.

Example 19

This example describes the synthesis of

which was prepared by treating a solution of compound 18 (Example 18) inDCM/TFA (1:1 ratio) with triethylsilane (10 equivalent). After LC-MSshowed that the starting material was completely consumed, the reactionwas concentrated, and the residue was purified by reverse phase HPLC togive the title compound.

Example 19

This example describes the synthesis of

which was prepared according to Scheme 12 and the procedure below.

a) A solution of 1 equivalent of compound 18.7 (Example 18g) in THF at−40° C. was treated with 1.0 equivalent of isopropylmagnesium bromide.After 0.5 hour, DMF (5 equivalents) was added, and the reaction waswarmed to room temperature over night. The reaction mixture was dilutedwith ethyl acetate and washed with water, brine. The organic layer wasthen dried with MgSO₄, filtered, and concentrated in vacuo. The residuewas then purified on silica gel column chromatography (gradient elutionusing ethyl acetate and hexanes) to provide pure compound 20.1.

b) To a solution of aldehyde 20.1 (1 equivalent) in THF at −78° C. wasadded 2.1 equivalents of ethnyl magnesium bromide (0.5 M in THF). Afterthe reaction was warmed to room temperature and stirred for anadditional 2 hours. The resulting reaction mixture was diluted withethyl acetate and washed with water. The organic layer was then driedwith MgSO₄, filtered, and concentrated in vacuo. The residue was thenpurified on silica gel column chromatography (gradient elution usingethyl acetate and hexanes) to provide pure compound 20.2.

c) 1 equivalent of compound 20.2, 1 equivalent of1-chloro-4-iodobenzene, 0.05 equivalent of CuI, and 5 equivalents oftriethylamine were dissolved in benzene and the solution degassed bybubbling N₂ thru a syringe needle and into the solution for 15 minutes.0.05 equivalent of PdCl₂(dppf).DCM was added. After 4 hours, thereaction was diluted with ethyl acetate and washed with water, brine.The organic layer was then dried with MgSO₄, filtered, and concentratedin vacuo. The residue was then purified on silica gel columnchromatography (gradient elution using ethyl acetate and hexanes) toprovide pure compound 20.3.

d) 1 equivalent of compound 20.3 was dissolved in MeOH. 5% Rh/Al₂O₃ wasadded. Under reduced pressure, oxygen was removed from the flask. Theinternal pressure was restored by the addition of hydrogen gas deliveredusing a hydrogen filled balloon. The reaction was stirred under anatmosphere of hydrogen gas for 14 hours. The reaction was filtered thrua pad of celite and concentrated in vacuo. The residue was then purifiedon silica gel column chromatography (gradient elution using ethylacetate and hexanes) to provide pure compound 20.4.

e) 4 equivalents of LiI was added to 1 equivalent of compound 20.4 inpyridine. The reaction was refluxed for 14 hours, then allowed to coolto room temperature. The reaction was concentrated and the resultingresidue was partitioned between ethyl acetate and water. The aqueouslayer was extracted with ethyl acetate. The combined organic layers weredried over MgSO₄, filtered, and concentrated. The residue was thenpurified on silica gel column chromatography (gradient elution usingethyl acetate and methanol) to provide pure compound 20.5.

f) 1 equivalent of compound 20.5, 1 equivalent of compound 8.4 (Example8c or 8e), and 3 equivalents of DIEA were dissolved in DMF. 1.1equivalent of HATU was added. The reaction was stirred at roomtemperature for 14 hours. The reaction mixture was diluted with ethylacetate and washed with water, brine. The combined organics were driedwith MgSO₄, filtered, and concentrated. The residue was then purified onsilica gel column chromatography (gradient elution using ethyl acetateand hexanes) to provide pure compound 20.6.

g) 1 equivalent of compound 20.6 was dissolved in methanol followed by 2equivalents of 1M LiOH(aq). Upon completion, the excess solvents wereremoved under reduced pressure and the resulting acid was then purifiedby reverse phase HPLC and lyophilized to a pure powder compound 20.

Example 21

This example describes the synthesis of

which was prepared according to Scheme 13 and the procedure below.

a) A solution of bromine (461 μL, 9.00 mmol) in methanol (6.0 mL) wasprepared at −78° C. The cold solution was added dropwise to a mixture ofKCN (1.85 g, 19.0 mmol) in methanol (6.0 mL) under nitrogen at −78° C.After 20 minutes, a solution of pyrrole (0.624 mL, 9.00 mmol) inmethanol (20 mL) was added. The mixture was allowed to reach −40° C. andstirred for 0.5 hour. It was then poured into ice-water and extractedwith ether (3×). The organic layers were combined and washed withsaturated sodium thiosulfate and brine. The organic phase was then dried(Na₂SO₄) and concentrated. The crude residue was purified by flashchromatography (0-50% ethyl acetate in hexane) to yield 734 mg (66%) ofcompound 21.1 as a clear oil, R_(f) 0.24 (10% ethyl acetate in hexane).¹H NMR (CDCl₃) δ 8.68 (br s, 1H), 7.03 (s, 1H), 6.69 (s, 1H), 6.32 (s,1H). ES (+) MS m/e=125 (M+H)⁺.

b) To a solution of 21.1 (614 mg, 4.95 mmol) and iodomethane (0.340 mL,5.45 mmol) in methanol (40 mL) under nitrogen at −10° C. was addeddropwise aqueous sodium hydroxide (9.90 mL, 1 M, 9.90 mmol). The mixtureis warmed to ambient temperature and stirred for 0.5 h. Excess sodiumhydroxide is then quenched by the addition of dry ice. The mixture isdiluted with brine and extracted with dichloromethane (3×). The combinedorganic layers are dried (Na₂SO₄) and concentrated to yield 504 mg (90%)of compound 21.2 as a dark oil, R_(f) 0.35 (10% ethyl acetate inhexane). ¹H NMR (CDCl₃) δ 8.31 (br s, 1H), 6.84 (s, 1H), 6.38 (s, 1H),6.24 (s, 1H), 2.36 (s, 3H).

c) To a 0° C. solution of compound 21.2 (100 mg, 0.884 mmol) in methanol(4.0 mL) was added dropwise sodium periodate (208 mg, 0.972 mmol) inwater (4.0 mL). The mixture is allowed to reach room temperature andafter 15 minutes LC/MS and TLC indicated complete disappearance ofcompound 21.2. The mixture was then filtered, concentrated, and theresidue was partitioned between ethyl acetate and water. The aqueouslayer was extracted twice with ethyl acetate and the combined organicphases were washed with brine, dried (Na₂SO₄) and concentrated to yield63 mg (55%) of compound 21.3 as a dark oil, R_(f) 0.25 (ethyl acetate).¹H NMR (CDCl₃) δ 11.74 (br s, 1H), 7.00 (s, 1H), 6.65 (s, 1H), 6.20 (s,1H), 3.03 (s, 3H). ES (+) MS m/e=130 (M+H)⁺.

d) To a solution of compound 21.3 (60 mg, 0.464 mmol) in dichloromethane(2.0 mL) was added trifluoroacetic acid (1.0 mL). After 15 minutes,LC/MS and TLC indicated complete consumption of compound 21.3. Thesolvent was removed in vacuo and the residue was dried under high vacuumto yield 60 mg (100%) of compound 21.4 as an oil, R_(f) 0.11 (ethylacetate). ¹H NMR (CDCl₃) δ 9.16 (br s, 1H), 7.28 (s, 1H), 6.94 (s, 1H),6.66 (s, 1H), 3.02 (s, 3H). ES (+) MS m/e=130 (M+H)⁺.

e) To a mixture of compound 21.4 (60 mg, 0.464 mmol) and Cs₂CO₃ (378 mg,1.16 mmol) was added a solution of compound 21.5 (Ferreira et al,Tetrahedron Letters, 39: 9575 (1998); 140 mg, 0.464 mmol) inacetonitrile. The resulting mixture was stirred at 60° C. until LC/MSand TLC indicated complete consumption of the starting material (˜1hour). The mixture was cooled to room temperature, diluted with ethylacetate and washed with water and brine. The organic layer was dried(Na₂SO₄) and concentrated. The crude residue was purified by flashchromatography (0-100% ethyl acetate in hexane) to yield 114 mg (57%) ofcompound 21.6 as a viscous oil, R_(f) 0.31 (ethyl acetate). ¹H NMR(CDCl₃) δ 7.05 (s, 1H), 6.75 (s, 1H), 6.50 (s, 1H), 5.25 (m, 1H), 4.65(m, 1H), 4.40 (m, 1H), 3.79 (s, 3H), 2.79 (s, 3H), 1.47 (s, 18H). ES (+)MS m/e=275 (M-Boc-t-Bu+2 H)⁺.

f) To a solution of compound 21.6 (114 mg, 0.265 mmol) indichloromethane (1.00 mL) is added mCPBA (89.0 mg, 0.397 mmol)portionwise. After 5 minutes at room temperature, LC/MS and TLCindicated complete disappearance of compound 21.6. The mixture wasfiltered and concentrated. The crude residue was purified by flashchromatography (0-50% ethyl acetate in hexane) to yield 89.0 mg (75%) ofcompound 21.7 as a clear oil, R_(f) 0.45 (50% ethyl acetate in hexane).¹H NMR (CDCl₃) δ 7.22 (s, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 5.27 (m, 1H),4.65 (m, 1H), 4.45 (m, 1H), 3.79 (s, 3H), 305 (s, 3H), 1.48 (s, 18H). ES(+) MS m/e=247 (M-2 Boc+3H)⁺.

g) To a solution of compound 21.7 (89.0 mg, 0.0.199 mmol) indichloromethane (0.50 mL) was added HCl (4.00 mL, 4.0 M in dioxane). Theresulting mixture was stirred at ambient temperature until LC/MSindicated complete deprotection (˜1 hour). The mixture was concentratedand the residue was dried under high-vacuum to yield 53 mg (100%) ofcompound 21.8 as white powder. ES (+) MS m/e=247 (M+H)⁺.

h) A mixture of compound 21.8 (53.0 mg, 0.199 mmol), compound 4.1(Example 4a, 77.0 mg, 0.199 mmol), HATU (79.0 mg, 0.209 mmol), andtriethyl amine (0.111 mL, 0.796 mmol) in DMF (1.00 mL) was stirred atroom temperature over night. The mixture was then diluted with ethylacetate and washed with 1.0 M aqueous HCl, saturated NaHCO₃, and brine.The organic layer was dried (Na₂SO₄) and concentrated. The crude residuewas purified by flash chromatography (0-100% ethyl acetate in hexane) toyield 70.3 mg (58%) of compound 21.9 as a white solid, R_(f) 0.16 (75%ethyl acetate in hexane). ¹H NMR (CDCl₃) δ 7.46-7.39 (m, 5H), 7.28 (s,1H), 6.73 (s, 1H), 6.69 (br s, 1H), 6.48 (s, 1H), 5.13 (m, 1H), 4.83 (brs, 1H), 4.56 (m, 1H), 3.85 (s, 3H), 3.70 (m, 1H), 3.04 (s, 3H), 2.91 (brs, 2H), 2.81 (s, 2H). ES (+) MS m/e=614 (M+H)⁺.

i) To a solution of 21.9 (70.3 mg, 0.115 mmol) in THF (1.00 mL) wasadded LiOH (aqueous 1.0 M, 0.360 mL, 0.360 mmol). The resulting mixturewas stirred at room temperature until TLC and LC/MS indicated completehydrolysis (˜0.5 hour). The reaction was then quenched by the additionof 1.0 M aqueous HCl (0.400 mL) and concentrated to dryness. The residuewas taken up in dimethylsulfoxide (“DMSO”; 4.0 mL) and purified bypreparative RP-HPLC. The fractions containing pure compound wereconsolidated and concentrated. The residue was lyophilized underhigh-vacuum for 48 hours to yield 33.8 mg (49%) of compound 21 as awhite powder. ¹H NMR (CDCl₃) δ 7.46-7.39 (m, 4H), 7.28 (m, 2H), 7.15 (brs, 1H), 6.77 (s, 1H), 6.38 (s, 1H), 5.74 (br s, 2H), 5.04 (m, 1H), 4.83(br s, 1H), 4.53 (m, 3H), 3.69 (m, 1H), 3.00 (s, 3H), 2.85 (br s, 2H).ES (+) MS m/e=600 (M+H)⁺.

Example 22

This example describes the synthesis of

which was prepared according to Scheme 14 and the procedure below.

a) A solution of 5.0 g (28.2 mmol) of compound 22.1 (Plobeck et al., J.Med. Chem. 43:3878-3894 (2000)) and sulfuryl chloride (100 mmol each,added at the beginning of the reaction and after 15 hours) in aceticacid (50 mL) was refluxed for 36 hours. The off white solid afterconcentration of the reaction mixture was rinsed with ether, and to theresulting crude product was added DCM (50 mL), followed by BBr₃ (1.0 Min DCM, 100 mL). After 6 hours, the reaction mixture is concentrated,and water (50 mL) was carefully added. The resulting precipitate iscollected by suction filtration and dried to give crude compound 22.2 inquantitative yield.

b) The crude compound 22.2 was dissolved in DCM/pyridine (50 mL/50 mL)and cooled to 0° C. To it was slowly added triflic anhydride (42.3mmol), and the reaction was then stirred at room temperature for 6hours. The reaction mixture was partitioned between ethyl acetate (200mL) and water (50 mL), and the organic layer was washed with water (30mL, twice) and brine, dried over anhydrous sodium sulfate and filtered.The residue after concentration of the filtrate was purified by silicagel column chromatography to give compound 22.3 (3.16 g, 32%). ESI-MS(m/z): (M+H⁺) 364/366.

c) Carbon monoxide gas was bubbled through a mixture of compound 22.3(581 mg, 1.6 mmol), BiNAP (0.2 mmol), palladium acetate (0.2 mmol),triethylamine (1 mL), anhydrous methanol (3 mL) and anhydrous DMF (3 mL)for 10 min, then the reaction was heated at 65° C. under a carbonmonoxide balloon for 15 hours. The reaction mixture was partitionedbetween ethyl acetate (100 mL) and water (25 mL), and the organic layerwas washed with water (25 mL, twice) and brine, dried over anhydrousmagnesium sulfate and filtered. The residue after concentration of thefiltrate was purified by silica gel column to give compound 22.4 (213mg, 49%). ESI-MS (m/z): (M+H⁺) 274/276.

d) To a suspension of sodium hydride (24 mg, 1.0 mmol) in THF (2 mL) wasadded compound 22.4 (63 mg, 0.23 mmol), 4-chlorobenzyl chloride (55 mg,0.34 mmol) and tetrabutylammonium iodide (10 mg). After 6 hours, thereaction was diluted with ether and filtered through silica gel, rinsedwith ether. The residue after concentration of the filtrate was purifiedby silica gel column to give compound 22.5 (50 mg, 55%). ESI-MS (m/z):(M+H⁺) 398/400.

e) A mixture of compound 22.5 (50 mg) and 1 mmol of LiI in 2 mL ofpyridine was reflux overnight. The reaction was concentrated in vacuoand the residue was further dried by high vacuum for 2 hour. Theresulting crude compound 22.6 was used without further purification.ESI-MS (m/z): (M+1), 384.

f) Compound 22 was prepared according to Example 3g except that compound22.6 was used instead of compound 3.7 (yield: 82%). ¹H NMR (400 MHz,dmso-d₆): 9.12 (d, 1H), 8.54 (t, 1H), 7.90 (s, 1H), 7.77 (dd, 1 H), 7.72(dd, 1H), 7.42 (d, 2H), 7.35 (d, 2H), 7.16 (dd, 1H), 4.77 (m, 1H), 4.70(s, 2H), 3.64 (m, 2H), 3.53 (t, 2H), 3.01 (t, 2H) ppm. ESI-MS (m/z):(M+H⁺) 580.

Example 23

This example describes the synthesis of

which was prepared according to Scheme 15 and the procedure below.

a) To a solution of Trit-Ser-Ome (compound 23.1, 10 mmol) andtriethylamine in DCM (40 mL) was added slowly methanesulfonyl chloride(11 mml), after 12 hours, the reaction was extracted with ether (100mL), washed with water, dried over anhydrous magnesium sulfate andfiltered. Concentration of the filtrate gave compound 23.2, which wasused without further purification.

b) Solution of the crude compound 23.2, sodium azide (20 mmol) in DMFwas stirred for 15 hours. The reaction was extracted with ether (100mL), washed with water, dried over anhydrous magnesium sulfate andfiltered. The residue after concentration of the filtrate was purifiedby column, eluting with 0-20% ethyl acetate in hexane to give compound23.3.

c) A mixture of 1 mmol of compound 23.3, 1.5 mmol ofcyclopropylacetylene, 0.02 mmol of CuI, and 0.02 mmol of Et₃N in 6 mL ofCH₃CN was stirred at room temperature overnight. The solvent was removedand the residue was purified to give compound 23.4 in 65% yield. ¹HNMR(400 MHz, CD₃OD): δ 7.80 (s, 1H), 7.29-7.31 (m, 6H), 7.15-7.23 (m, 9H),4.49 (m, 2H), 3.73 (m, 1H), 3.16 (s, 3H), 1.99 (m, 1H), 0.99 (m, 2H),0.80 (m, 2H) ppm; ESI-MS (m/z): (M+H⁺) 453.15.

d) A mixture of 0.5 mmol of compound 23.4 in 2 mL of 4.0 N HCl indioxane was stirred at room temperature for 1 hours. The solvent wasremoved and the residue was diluted with 10 mL of water. The mixture wasextracted with ether for 3 times, and the aqueous phase was dried withlyophilizer to give compound 23.5 in quantitative yield. ESI-MS (m/z):(M+H⁺) 212.15.

e) Compound 23 was prepared according to Example 3g except that compound4.4 was used instead of compound 3.7 and compound 23.5 was used insteadof compound 3.4. ¹H NMR (400 MHz, CD₃OD): δ 7.74 (s, 1H), 7.33 and 7.49(m, 5H), 5.25 (m, 1H), 4.63-4.92 (m, 4H), 3.99 and 3.68 (m, 2H), 2.89(m, 2H), 1.91 (m, 1H), 0.95 (m, 2H), 0.75 (m, 2H) ppm; ESI-MS (m/z):(M+H⁺) 562.10.

Example 24

This example describes the synthesis of

which was prepared according to Scheme 16 and the procedure below.

a) To a solution of 50 mmol of 1-bromo-3,5-difluorobenzene in 100 mL ofdry DMF was added 50 mmol of NaSCH3 at 0° C., the resulting mixture wasstirred at room temperature overnight and treated with 10 mL ofsaturated aqueous NH₄Cl. The mixture was diluted with 1 L of water,extracted with hexane for several times. The extract was washed withwaster and dried with anhydrous Na₂SO₄. The solvent was removed and theresidue was purified to give compound 24.2 in 90% yield. ¹H NMR (400MHz, CD₃Cl): δ 7.15 (s, 1H), 7.02 (d, J=8.3 Hz, 1H), 6.89 (d, J=9.2 Hz,1H), 2.50 (s, 3H) ppm.

b) A mixture of 40 mmol of compound 24.2 and 42 mmol of CuCN in 100 mLof dry DMF was stirred at 150° C. overnight. The mixture was dilutedwith 500 mL of water, extracted with ether for several times. Themixture was then washed with diluted aqueous NH₄OH and water and driedwith anhydrous Na₂SO₄. The solvent was removed; the residue was purifiedto give compound 24.3 in 50% yield. ¹H NMR (400 MHz, CD₃Cl): δ 7.28 (s,1H), 7.17 (d, J=9.2 Hz, 1H), 7.11 (d, J=6.8 Hz, 1H), 2.53 (s, 3H) ppm;ESI-MS (m/z): (M+H⁺) 168.0.

c) A mixture of 20 mmol of compound 24.3 and 22 mmol of KOH in 25 mL ofEtOH and 35 mL of H₂O was stirred at 60° C. for 30 minutes. The mixturewas concentrated, the residue was diluted with 100 mL of water,extracted with EtOAc for several time. The extract was dried withanhydrous Na₂SO₄. The solvent was removed and the residue was dried invacuo to give a crude product of compound 24.4. The crude was carried onthe next step without further purification. ESI-MS (m/z): (M+H⁺) 187.0.

d) To a solution of 20 mmol of compound 24.4 in 60 mL of dry THF wasadded 24 mmol of LiAlH₄ (1.0 M in THF) at 0° C. After stirring at roomtemperature overnight, the reaction mixture was carefully addedsaturated aqueous NH₄Cl. The resulting suspension was then concentrated.The residue was dissolved in 200 mL of 1.0 N HCl and extracted withEtOAc for several times. The extract was dried with anhydrous Na₂SO₄ andconcentrated. Subsequently, the residue was purified to give5-fluoro-3-methylmercapto-1-benzeyl alcohol in 81% yield. ¹H NMR (400MHz, CD₃Cl): δ 7.03 (s, 1H), 6.86 (m, 2H), 4.69 (s, 2H), 2.51 (s, 3H)ppm; ESI-MS (m/z): (M+H⁺) 173.1.

A mixture of 15 mmol of 5-fluoro-3-methylmercapto-1-benzeyl alcohol and20 mmol of SOCl₂ in 30 mL of dry CH₂Cl₂ was refluxed for several hours.The mixture was then diluted with 100 mL of CH₂Cl₂, washed withsaturated aqueous NaHCO₃, saturated aqueous NH₄Cl, and brine and driedwith anhydrous Na₂SO₄. The solvent was removed and the residue waspurified to give compound 24.5 in 85% yield.

e) Compound 24.6 was prepared according to Example 3a-c except thatcompound 24.5 was used instead of 3-methylthiobenzyl chloride.

f) Compound 24 was prepared according to Example 3g except that compound24.6 was used instead of compound 3.7. ¹H NMR (400 MHz, CD₃OD): δ 7.92(s, 1H), 7.80 (s, 1H), 7.75 (d, J=7.83 Hz, 1H), 7.74 (s, 1H), 7.59 (d,J=7.34 Hz, 1H), 7.49 (d, J=9.29 Hz, 1H), 7.07 and 7.35 (m, 2H), 6.96 (s,1H), 5.10 (dd, J=9.78, 4.40 Hz, 1H), 4.72 and 4.91 (m, 2H), 3.77 and4.00 (m, 2H), 3.50 (dd, J=14.18, 4.40 Hz, 1H), 3.20 (m, 1H), 2.91 (m,2H) ppm; ESI-MS (m/z): (M+H⁺) 633.10.

Example 25

This example describes the synthesis of

which was prepared according to Scheme 17 and the procedure below.

a) To a solution of 5.0 mmol of compound 3.2 (Example 3a), 0.25 mmol ofPd(PPh₂)₂Cl₂, and 0.25 mmol of CuI in 15 mmol of degassed Et₃N and 40 mLof degassed toluene was added 5.5 mmol of isobutyryl chloride at 0° C.The resulting mixture was stirred at room temperature overnight andtreated with 20 mL of saturated aqueous NaHCO₃. The organic layer wasseparated and dried with anhydrous Na₂SO₄. The solvent was removed andthe residue was purified by column chromatography to give compound 25.1in 80% yield. ¹H NMR (400 MHz, CD₃OD): δ 4.38 (m, 1H), 3.74 (s, 3H),2.91 (m, 2H), 2.61 (m, 1H), 1.44 (s, 9H), 1.14 (d, J=6.85 Hz, 6H) ppm;ESI-MS (m/z): (M+H⁺) 320.01.

b) To a solution of 1.0 mmol of compound 25.1 in 3 mL of CH₃OH was added1.0 mmol of NH₂NH₂ at 0° C., the resulting mixture was stirred foranother 30 minutes. The solvent was removed, and the residue waspurified give compound 25.2 in 65% yield.

¹H NMR (400 MHz, CD₃OD): 6.28 and 5.95 (s, s, 1H), 4.39 and 4.19 (m,1H), 3.72 (s, 3H), 2.91 (m, 2H), 2.70 and 2.98 (m, 1H), 1.43 and 1.45(s, s, 9H), 1.12 and 1.27 (m, 6H) ppm; ESI-MS (m/z): (M+H⁺) 312.20.

c) A mixture of 0.5 mmol of compound 25.2 in 4 mL of 4.0 N HCl indioxane was stirred at room temperature for 12 hours. The solvent wasremoved and the residue was dried in vacuo to give compound 25.3. ESI-MS(m/z): (M+H⁺) 212.10.

d) Compound 25 was prepared according to Example 3g except that compound4.4 was used instead of compound 3.7 and compound 25.3 was used insteadof compound 3.4.

¹H NMR (400 MHz, CD₃OD): 7.15-7.54 (m, 5H), 6.38 (s, 1H), 5.06 (dd,J=9.78, 4.89 Hz, 1H), 4.66 and 4.88 (m, 2H), 4.01 and 3.71 (m, 2H), 3.41(dd, J=15.41, 4.65 Hz, 1H), 3.18 (dd, J=15.16, 4.65 Hz, 1H), 3.07 (m,1H), 2.92 (m, 2H), 1.32 (d, J=7.34 Hz, 6H) ppm; ESI-MS (m/z): (M+H⁺)563.10.

Example 26

This example describes the synthesis of

which was synthesized according Scheme 18 and the procedure below.

a) A solution of compound 26.1 (12.4 g, 75 mmol) and NH₄BF₄ (10.5 g, 100mmol) in water (85 mL) was treated with concentrated HCl (15 mL), cooledto 3° C., and treated dropwise over 25 minutes with a solution of NaNO₂(5.18 g, 75 mmol) in water (12 mL). The resulting thick slurry wasstirred for 35 minutes, and the solid was collected by filtration,rinsed with water, methanol, and ether, and dried under N₂. The solidwas added in one portion to a stirred mixture of KOAc (8.1 g, 82.5 mmol)and 18-crown-6 (0.5 g, 1.9 mmol) in chloroform (170 mL). After 70minutes, water (170 mL) was added, and the layers were separated. Theaqueous phase was extracted with chloroform, and the combined organiclayers were rinsed with water, dried, and concentrated. The residue wastriturated with hexane and the resulting solid isolated by filtration toprovide 8.85 g (67% yield) of compound 26.2 as a dull yellow powder. ¹HNMR (CDCl₃) δ 3.96 (s, 3H), 7.80-7.85 (m, 2H), 8.14 (s, 1H), 8.27 (s,1H); ES (+) MS m/e=177 (M+1).

b) A solution of compound 26.2 (5.0 g, 28.4 mmol) in THF (56 mL) wastreated with LiOH (21 mL of a 2M aqueous solution, 42 mmol), and thereaction mixture is stirred at 50° C. After 4 hours, the reactionmixture was cooled to room temperature and diluted with water. The basicaqueous layer was rinsed with diethyl ether, acidified to pH 3-4 by theaddition of 1 M HCl, and extracted with ethyl acetate. The aqueous layerwas extracted further with ethyl acetate, and the combined organiclayers were rinsed with brine, dried over MgSO₄, and concentrated toafford 4.0 g (87% yield) of compound 26.3. ¹H NMR (CD₃OD) δ 7.79-7.87(m, 2H), 8.14 (s, 1H), 8.29 (s, 1H); ES (+) MS m/e=163 (M+1).

c) A solution of compound 1.1 (7.5 g, 20.8 mmol) in DCM (30 mL) wastreated with TFA (10 mL). After 1 hour, the reaction mixture wasconcentrated to afford 7.8 g (100% yield) of compound 26.4. ES (+) MSm/e=261 (M+1).

d) A solution of compound 26.3 (7.8 g, 20.8 mmol), compound 26.4 (3.4 g,20.8 mmol), 1-hydroxybenzotriazole hydrate (“HOBt”, 3.5 g, 22.3 mmol),and diisopropylethylamine (“DIEA”, 14 mL, 83.3 mmol) in DMF (100 mL) wastreated with EDCI (4.4 g, 22.3 mmol). After 2 h, the reaction mixturewas treated with 1 M HCl and extracted with ethyl acetate. The combinedorganic extracts were rinsed with NaHCO₃ (sat'd), rinsed with brine,rinsed with water, dried over MgSO₄, and concentrated to afford 8.4 g(99% yield) of the title compound. ES (+) MS m/e=404 (M+1).

e) A solution of compound 26.5 (8.4 g, 20.8 mmol) in pyridine (70 mL)was treated with lithium iodide (11.1 g, 83.1 mmol), and the reactionmixture was heated to 100° C. After 16 hours, the reaction mixture wascooled to room temperature and diluted with 1 M NaOH (aq). The basicaqueous layer was rinsed with diethyl ether to remove most of thepyridine. The aqueous portion was then carefully acidified withconcentrated HCl to pH 3-4. The resulting slurry was filtered. Theprecipitate was collected and dissolved in THF, while the filtrate wasextracted with ethyl acetate. The THF and ethyl acetate solutions werecombined, rinsed with brine, dried over MgSO₄, and concentrated toafford 7.1 g (88% yield) of compound 26.6. ES (+) MS m/e=390 (M+1).

f) A solution of compound 26.6 (3.06 g, 7.83 mmol) and DIEA (4.6 mL,25.4 mmol) in dimethylformamide (“DMF”) was treated with HATU (3.06 g,8.06 mmol), and the resulting mixture was stirred at room temperature.After 20 minutes, the reaction mixture was treated sequentially withHCl.H-DAP(Boc)-OMe (2.18 g, 8.59 mmol) and N,N-dimethylaminopyridine(“DMAP”, 0.568 g, 4.65 mmol). After 2.5 hours, the reaction was dilutedwith ethyl acetate, washed with three portions of water, washed with oneportion of brine, dried over MgSO₄, and concentrated. Flash columnchromatography afforded 3.91 g (84% yield) of compound 26.7. ¹H NMR (400MHz, chloroform-d) δ: 1.42 (s, 9H), 2.81 (s, 2H), 3.70 (m, 2H), 3.75(2H), 3.81 (s, 3H), 4.82 (m, 21H), 4.99 (m, 1H), 7.21 (d, 2H), 7.59 (s,1H), 7.81 (d, 1H), 8.10 (s, 1H). MS (API-ES⁺) m/z: 590.2 (M+H⁺), 534.1(M-tButyl+H⁺), 490.1 (M-Boc+H⁺).

g) A solution of compound 26.7 (3.91 g, 6.62 mmol) in DCM was treatedwith HCl (8.3 mL of a 4 M dioxane soln, 33.2 mmol), and the resultingmixture was stirred at room temperature. After 2 hours, the reactionmixture was concentrated to afford the HCl salt, which was used withoutfurther purification. The HCl salt (3.94 g, 6.99 mmol) and triethylamine(“TEA”, 3.0 mL, 21.5 mmol) in methanol was treated withN-cyanoimido-S,S-dimethyl-dithiocarbonate (1.37 g, 8.43 mmol), and thereaction mixture was stirred at 50° C. After 3.5 hours, the reactionmixture was concentrated to remove most of the methanol, diluted withethyl acetate, washed with two portions of water, washed with oneportion of brine, dried over MgSO₄, and concentrated. Flash columnchromatography afforded 3.27 g (80% yield) of compound 26.8 (MS(API-ES⁺) m/z: 588.2 (M+H⁺). A solution of compound 26.8 (0.10 mmol) wasmade in 4:1 methanol/dichloroethane (“DCE”, 2.5 mL) and treatedsequentially with 2 M methanolic ammonia (0.25 mmol) and silver nitrate(0.10 mmol). The reaction mixture was stirred at 50° C. until completeconversion is observed through monitoring by LCMS. The reaction mixturewas then filtered through celite, and KOH (0.1 mL of a 2 M methanolicsoln, 0.2 mmol) was added. The reaction mixture was stirred once againat 50° C. After 2-4 hours the reaction mixture was directly subjected topreparatory HPLC purification to afford compound 26.

Example 27

This example describes the synthesis of

where R^(A) and R^(B) are each independently hydrogen, aliphatic,aromatic, heteroaromatic, or together form a cyclic moiety. Thesecompounds are made according to the procedure of Example 26 except thata substituted amine of the formula HNR^(A)R^(B) is used instead ofammonia in step g. Illustrative examples of substituted amines and theresulting compounds are shown in Table 1.

TABLE 1 HNR^(A)R^(B) Compound

Example 28

This example describes the synthesis of

which is made according to Scheme 19 and the procedure below.

a) Compound 28.4 is prepared from 28.1 in three chemical steps,following the procedure published in Okada, T. et al Chem. Phar. Bull.1993, 41(1), 126-131; Frigola, J. et al J. Med. Chem. 1993, 36(7),801-810 as shown above. A solution of commercially available 28.1 in DCMis treated with trifluoromethanesulfonyl chloride in the presence ofbase to provide 36.2. Next, this product is dissolved in dimethoxyethane(“DME”), and the mesylate moiety is displaced by dimethylamine Finally,Pd/C-catalyzed hydrogenolysis in MeOH at 45 PSI H₂ (g) affords compound28.4.

b) Compound 28 is synthesized according to the procedure of Example 26except 3-(dimethylamino)cyclobutanol (35.1) is used instead of ammoniain step g.

Example 29

This example describes the synthesis of

which is made according to Scheme 20 and the procedure below.

a) To a solution of benzyl-3-pyrroline-1-carboxylate (compound 29.1, 10mmol) in THF (15 mL) was added N-methyl morpholine (22 mmol) and O_(S)O₄(2 mL of a 2.5 wt % in t-BuOH), and the resulting mixture was stirred atroom temperature overnight. The solvent was removed; the residue wasdissolved in EtOAc (100 mL), washed with dilute aq. Na₂SO₃, sat. aq.NH₄Cl, and brine, and dried with anhydrous Na₂SO₄. The solvent wasremoved and the residue was purified by column chromatography to givecompound 29.2 in 55% yield. EIMS (m/z): calcd. for C₁₂H₁₅NO₄ (M⁺)+Na260.1. Found 260.1; ¹H NMR (CD₃OD, 400 MHz): δ 7.31-7.38 (m, 5H), 5.13(s, 2H), 4.17 (m, 2H), 3.58 (m, 2H), 3.34 (m, 2H) ppm.

b) A mixture of compound 29.2 (1.0 mmol) and 10% Pd/C (0.1 mmol) inmethanol (5 mL) is stirred at room temperature for several hours underan atmosphere of H₂. The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to give compound 29.3.

c) Compound 29 is synthesized according to the procedure of Example 26except that (3R,4S)-(dihydroxy)pyrrolidine (29.3) is used instead ofammonia in step g.

Example 30

This example describes the synthesis of

which was prepared according to Scheme 21 and the procedure below.

a) A mixture of (3R,4R)-benzyl-3,4-pyrrolidinediol (compound 30.1, 1mmol) and 20% Pd(OH)₂/C (0.1 mmol) in methanol (10 mL) is shaken at roomtemperature for several hours under 45 psi of H₂. (g). The reactionmixture is filtered, the filtrate is concentrated, and the residue isdried in vacuo to give compound 30.2.

b) Compound 30 is synthesized according to the procedure of Example 26except that compound 30.2 is used instead of ammonia in step g.

Example 31

This example describes the synthesis of

which was prepared according to Scheme 22 and the procedure below.

a) A mixture of commercially available benzyl 3-pyrroline-1-carboxylate(compound 28.1, 10 mmol) and m-CPBA (12 mmol) in DCM (50 mL) was stirredat room temperature overnight. The reaction mixture was diluted with DCM(100 mL) and washed sequentially with sat. aq. Na₂SO₃, and brine. Theorganic layer was dried with anhydrous Na₂SO₄ and then concentrated. Theresidue was purified by chromatography to give compound 31.1 in 80%yield. EIMS (m/z): calcd. for C₁₂H₁₃NO₃ (M⁺)+Na 242.1. Found 242.1; ¹HNMR (CDCl₃, 400 MHz): δ 7.36-7.37 (m, 5H), 5.13 (s, 2H), 3.89 (m, 2H),3.70 (m, 2H), 3.41 (m, 2H) ppm.

b) A mixture of compound 31.1 (5 mmol) in conc. aq. NH₃ (20 mL) isstirred at 65° C. overnight. The reaction mixture was concentrated anddried in vacuo to give compound 31.2. This material is used withoutfurther purification.

c) A solution of compound 31.2 (10 mmol) and Et₃N (20 mmol) in dry THF(100 mL) at −20° C. is treated dropwise with TFAA (10 mmol) over 1 hour.After 1 h, the reaction mixture is quenched with sat. aq. NH₄Cl (1 mL).The solvent is removed and the residue is dissolved in DCM (100 mL). Themixture is subsequently washed sequentially with sat. aq. NH₄Cl, sat.aq. NaHCO₃, and brine. The organic layer is dried with anhydrous Na₂SO₄,the solvent was removed, and the residue is purified by chromatographyto afford compound 31.3.

d) A solution of compound 31.3 (5 mmol) and Et₃N (10 mmol) dry DCM (20mL) at 0° C. is treated dropwise with MsCl (5.5 mmol), and the mixtureis allowed to come gradually to room temperature. After 1 hour at roomtemperature, the reaction mixture containing in situ generated 31.4 istreated with DBU (30 mmol), and the resulting mixture is stirred at forseveral hours. The solvent is removed, and the residue is purified bychromatography to afford compound 31.5.

e) A mixture of compound 31.5 (3 mmol) and K₂CO₃ (6 mmol) in 2/1 (v/v)MeOH/H₂O (15 mL) is stirred at room temperature. After 24 h, the solventis removed; the residue is treated with sat aq. NaHCO₃ (20 mL), and themixture is extracted with DCM several times. The extract is dried withNa₂CO₃., the solvent is removed, and the residue is purified bychromatography to afford compound 31.6.

f) A mixture of compound 31.6 (2 mmol), NaHCO₃ (3 mmol), and Boc₂O (2.2mmol) in 1:1 1,4-dioxane/water (20 mL) is stirred at room temperaturefor several hours. The mixture is diluted with brine (50 mL) andextracted with EtOAc several times. The combined extracts are washedwith brine, dried with anhydrous Na₂SO₄, and concentrated. The residueis purified by chromatography to give the N-Boc protected intermediate.A mixture of this intermediate (1 mmol) and 10% Pd/C (0.1 mmol) in MeOH(5 mL) is stirred at room temperature for several hours under anatmosphere of H₂ (g). The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to afford compound 31.7.

g) Compound 31 is prepared according to Example 26g except that compound31.7 is used instead of ammonia.

Example 32

This example describes the synthesis of

which is prepared according to Scheme 23 and the procedure below.

a) A mixture of compound 31.2 (2 mmol), NaHCO₃ (3 mmol), and Boc₂O (2.2mmol) in 1:1 1,4-dioxane/water (20 mL) is stirred at room temperaturefor several hours. The mixture is diluted with brine (50 mL) andextracted with EtOAc several times. The combined extracts are washedwith brine, dried with anhydrous Na₂SO₄, and concentrated. The residueis purified by chromatography to afford compound 32.3.

b) A mixture of compound 32.3 (1 mmol) and 10% Pd/C (0.1 mmol) in MeOH(5 mL) is stirred at room temperature for several hours under anatmosphere of H₂ (g). The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to afford compound 32.4.

c) Compound 32 is prepared according to Example 26g except that compound32.4 is used instead of ammonia.

Example 33

This example describes the synthesis of

which is prepared according to Scheme 24 and the procedure below.

a) A solution of compound 33.1 (10 mmol) and DIEA (25 mmol) in DCM (20mL) at 0° C. is treated dropwise with benzyl chloroformate (10 mmol),and the reaction mixture is allowed to come to room temperature. After 2h at RT, the reaction mixture is diluted with ethyl acetate (100 mL),rinsed with 1 M HCl (50 mL), rinsed with brine, dried over MgSO₄, andconcentrated to afford compound 33.2.

b) A solution of compound 33.2 (10 mmol) and N-methyl morpholine (22mmol) in THF (15 mL) is treated with O_(S)O₄ (2 mL of a 2.5 wt % int-BuOH), and the resulting mixture is stirred at room temperatureovernight. The solvent is removed. The residue is dissolved in EtOAc(100 mL), washed with dilute aq. Na₂SO₃, sat. aq. NH₄Cl, and brine, andthen dried over anhydrous Na₂SO₄. The solvent is removed, and theresidue is purified by column chromatography to give the title compound.

c) A mixture of compound 33.3 (1.0 mmol) and 10% Pd/C (0.1 mmol) inmethanol (5 mL) is stirred at room temperature for several hours underan atmosphere of H₂. The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to give compound 33.4.

d) Compound 33 is prepared according to Example 26g except that compound33.4 is used instead of ammonia.

Example 34

This example describes the synthesis of

which is prepared according to Scheme 25 and the procedure below.

a) A mixture of Tl(OAc) (17.6 g, 54.5 mmol) in dried acetic acid (40 mL)is refluxed with stirring for 1 hour and then cooled to roomtemperature. Compound 32.2 (34.6 mmol) and iodine (8.46 g, 33.3 mmol)are added, and the resulting suspension is heated to reflux. After 9hours, the reaction mixture is cooled to room temperature, and theyellow TlI precipitate is removed by filtration with ether rinses. Thefiltrate is concentrated, and the residue is dissolved in ethyl acetate,dried over MgSO₄, and reconcentrated to afford compound 34.1.

b) A mixture of 34.1 (1.0 mmol) and 10% Pd/C (0.1 mmol) in methanol (5mL) is stirred at room temperature for several hours under an atmosphereof H₂. The reaction mixture is filtered, the filtrate is concentrated,and the residue is dried in vacuo to give compound 34.2.

c) Compound 34 is prepared according to Example 26g except that compound34.2 is used instead of ammonia.

Example 35

This example describes the synthesis of

which is prepared according to Scheme 26 and the procedure below.

a) A mixture of compound 35.1 (10 mmol) in ethanol (20 mL) is saturatedwith HCl (g) and stirred at room temperature overnight. The solvent isremoved, the residue is dissolved in DCM (100 mL), the resultingsolution is treated sequentially with TEA (30 mmol) and BnBr (11 mmol),and the reaction mixture is heated to reflux. After 12 h, the reactionmixture is cooled to room temperature and concentrated. The residue isdissolved in EtOAc (150 mL), washed with brine, and dried over anhydrousNa₂SO₄. The solvent is removed and the residue is purified bychromatography to afford compound 35.2.

b) A solution of LiBH₄ (20 mmol) in dry THF (20 mL) at room temperatureis treated in a dropwise fashion with a solution of compound 35.2 (5mmol) in THF (5 mL). After stirring overnight, the reaction mixture isquenched by adding several drops of water. The mixture is concentrated,diluted with brine (50 mL), and extracted several times with 9/1 (v/v)EtOAc/i-PrOH. The combined extracts are dried over anhydrous Na₂SO₄, thesolvent is removed, and the residue is purified by chromatography toafford compound 35.3.

c) A solution of compound 35.3 (2 mmol) and TEA (2.2 mmol) in dry THF(10 mL) at −78° C. is treated dropwise with trifluoroacetic anhydride(“TFAA”, 2.2 mmol). After several hours, the mixture is treated with TEA(6 mmol), and the reaction mixture is heated to reflux. The mixture thenis concentrated, and the residue is dissolved in THF (10 mL) and treatedwith water (2.5 mL). This mixture is treated with NaOH (10 mmol) withvigorous stirring at room temperature for several hours. The solvent isremoved, and the residue is treated with sat. aq. NaHCO₃ (20 mL) andextracted several times with 9/1 (v/v) EtOAc/i-PrOH. The combinedextracts are dried over anhydrous Na₂SO₄, the solvent is removed, andthe residue is purified by chromatography to afford compound 35.4.

d) A mixture of compound 35.4 (1 mmol) and 20% Pd(OH)₂/C (0.1 mmol) inmethanol (10 mL) is shaken at room temperature for several hours under45 psi of H₂. (g). The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to give compound 35.5.

e) Compound 35 is prepared according to Example 26g except that compound35.5 is used instead of ammonia.

Example 36

This example describes the synthesis of

which was prepared according to Example 35 except that(2R,4S)-4-hydroxyproline (trans-D-Hyp-OH) was used instead of compound35.1.

Example 37

This example describes the synthesis of

which was prepared according to Example 35 except that(2S,4R)-4-hydroxyproline (trans-L-Hyp-OH) was used instead of compound35.1.

Example 38

This example describes the synthesis of

which is prepared in according to Scheme 27 and the procedure below.

a) A solution of HCl.H-DAP(Boc)-OMe (10 mmol) and DIEA (11 mmol) in DCM(50 mL) at 0° C. is treated dropwise with benzoyl chloride (11 mmol).Over 3 h the reaction mixture is allowed to warm to room temperature.The reaction mixture is concentrated, and the residue is purified bychromatography. This intermediate is treated with a solution of 4 M HClin dioxane, and the resulting mixture is stirred at room temperature.After 1 h, the solvent is removed to afford compound 38.1, which is usedwithout further purification.

b) A solution of compound 38.1 (10 mmol) and DIEA (12 mmol) in DCM (50mL) at 0° C. is treated dropwise with p-nitrophenyl chloroformate (11mmol), and the reaction mixture is allowed to warm to room temperature.After 2 hours, the reaction mixture is concentrated, and the residue ispurified by chromatography to afford compound 38.2.

c) A solution of compound 38.2 (10 mmol) and TEA (25 mmol) in 1:1DCE/DMF (10 mL) is treated with 2 M methanolic ammonia (18 mmol), andthe mixture is heated to 40° C. After 15 hours, the reaction mixture isconcentrated, and the residue is purified by chromatography to affordcompound 38.3.

d) A mixture of compound 38.3 (1.0 mmol) and 10% Pd/C (0.1 mmol) inmethanol (10 mL) is shaken at room temperature for several hours under45 psi of H₂. (g). The reaction mixture is filtered, the filtrate isconcentrated, and the residue is dried in vacuo to give compound 38.4.

e) A solution of compound 26.6 (8.0 mmol) and DIEA (25. mmol) in DMF istreated with HATU (8.0 mmol), and the resulting mixture was stirred atroom temperature. After 20 minutes, the reaction mixture is treatedsequentially with compound 38.4 (8.6 mmol) and DMAP (0.5 mmol), and themixture is then heated to 60° C. After 2.5 hours, the reaction isdiluted with ethyl acetate, washed with three portions of water, washedwith one portion of brine, dried over MgSO₄, and concentrated. Flashcolumn chromatography affords compound 38.5.

f) A solution of compound 38.5 (0.15 mmol) in methanol (1 mL) wastreated with 2 M methanolic KOH (0.45 mmol), and the reaction mixture isheated to 50° C. After 3 hours, the reaction mixture is concentrated todryness and the residue is subjected to preparatory HPLC purification toafford compound 38.

Example 39

This example describes the synthesis of

where R^(A) and R^(B) are each independently hydrogen, aliphatic,aromatic, heteroaromatic, or together form a cyclic moiety. Thesecompounds are made according to the procedure in Example 38 except thata substituted amine of the formula HNR^(A)R^(B) is used instead ofammonia in step c. Illustrative examples of substituted amines and theresulting compounds are shown in Table 2.

TABLE 2 HNR^(A)R^(B) Compound

Example 40

This example describes the synthesis of

which is prepared according to Scheme 28 and the procedure below.

a) Commercially available compound 40.1 (10 mmol) in THF (50 mL) istreated with sodium hydrosulfite (50 mmol) in water (20 mL). After 8hours at room temperature, the reaction is extracted with ethyl acetate(100 mL), and the organic extract is washed with water and brine, driedover anhydrous magnesium sulfate and filtered to give the crude compound40.2.

b) To a slurry of compound 40.2 (10 mmol), ammonium tetrafluoroborate(12.5 mmol) in water (12 mL) is added concentrated HCl (2 mL). Thereaction is cooled to 0° C., and to it is added sodium nitrite (10mmol). After the reaction is stirred for 1 hour at 0° C., the solid iscollected by filtration, rinsed with methol, ether and dried undervacuum. The resulting solid is added to a stirring solution of HOAc (3mL), 18-crown-6 (0.3 mmol) in chloroform (20 mL). After 1 hour, water(10 mL) and DCM (20 mL) are added. The organic layer is separated, driedby magnesium sulfate and filtered. The residue after concentration ofthe filtrate is triturated with hexane to give product 40.3.

c) Compound 40.4 was made according to the procedure for the preparationof compound 6.1 except that R-3-(+)-pyrrolidinol was used instead ofpyrrolidine.

d) Compound 40.4 is dissolved in DCM, and is treated with triethylamine(1.5 eq) and acetic anhydride (1.2 eq). The resulting solution isfiltered through silica gel, concentrated. The residue is then purifiedby silica gel column chromography to yield compound 40.5.

e) Compound 40.5 in DCM is treated with anhydrous 4 N HCl in dioxane(2.0 eq). After starting material disappears, the reaction isconcentrated to give compound 40.6.

f) Compound 40.7 is made according to the procedure for the preparationof compound 1.5 except that compound 40.6 is used instead of 1.3.

g) Compound 40.8 is made according to the procedure for the preparationof compound 1.6 except that compounds 40.7 and 40.3 are used instead ofcompounds 1.5 and 1.11.

h) Compound 40 is made according to the procedure for the preparation ofcompound 1 except that compound 40.8 is used instead of 1.6.

Example 41

This example describes the synthesis of

which is prepared according to Scheme 29 and the procedure below.

Compound 41 is made according to the procedure for the preparation ofcompound 3 except that compounds 18.10 and 40.6 are used instead of 3.4and 3.7. The enantiomerically pure compounds are isolated using chiralcolumn chromatography.

Example 42

This example describes the synthesis of

which is prepared according to Scheme 30 and the procedure below.

a) A solution of compound 18.7 (10 mmol), 1-ethoxy-1-ethenyltributyltin(10.5 mmol), Pd(PPh)₄ (0.5 mmol) in dimethoxyethane (DME, 50 mL) isheated at 80° C. until compound 18.7 disappears. The reaction is cooledto room temperature, and to it is added 4N aqueous HCl (5 mL). Thereaction is stirred for 3 hours and extracted with ether (80 mL). Theorganic extract is washed with brine, dried with anhydrous magnesiumsulfate, filtered and concentrated. The residue is purified by columnchromatography to give compound 42.1.

b) A solution of compound 42.1 in THF at −78° C. is treated with LDA(2.0 eq). After 1 hour, a solution of compound 18.2 (1.0 eq) in THF isadded to the dry ice cooled reaction. After another 3 hours, saturatedaqueous NH₄Cl is added to the reaction and the mixture is allowed towarm to room temperature. The reaction mixture is partitioned betweenethyl acetate and water, and the organic layer is washed with water andbrine, dried with anhydrous magnesium sulfate and filtered. The residueafter concentration of the filtrate is purified by silica gel column togive compound 42.2.

c) A solution of compound 42.2 in ethanol is treated with sodiumborohydride (2.0 eq). After 1 hour, the reaction mixture is partitionedbetween ethyl acetate and water, and the organic layer is washed brine,dried with anhydrous magnesium sulfate and filtered. The residue afterconcentration of the filtrate is purified by silica gel column to givecompound 42.3.

d) A mixture of 42.3 LiI (3 eq) in pyridine is reflux overnight. Thesolvent is removed and the residue is dissolved in EtOAc. The resultingsolution is then washed with saturated aqueous NH₄Cl and dried withanhydrous Na₂SO₄. The solvent is removed and the residue is dried invacuo to give a quantitative yield of compound 42.4. The crude productwas carried on the next step without further purification.

e) Compound 42 is made according to the procedure for the preparation ofcompound 3 except that compounds 42.4 and 40.6 are used instead of 3.4and 3.7. The enantiomerically pure compounds are isolated using chiralcolumn chromatography.

Example 43

This example describes the synthesis of

which is prepared according to Scheme 31 and the procedure below.

a) A solution of compound 18.2 in ethanol is treated with hydroxylamine(1.05 eq). After 10 hours, the reaction is concentrated and the residueis dried under vacuum to give compound 43.1.

b) A solution of 43.1 is hydrogenated with 20% Pd(OH)₂/C as a catalystat 45 psi of hydrogen to give compound 43.2.

c) A solution of commercially available 43.3 in carbon tetrachloride istreated with N-chlorosuccinimide (NCS, 3 eq). The reaction mixture isthen diluted with ethyl acetate, washed with 1N NaOH, water and brine,dried over anhydrous MgSO₄ and filtered. The crude product isrecrystallized from hot ethanol to give compound 43.4.

d) A solution of 43.4 in THF is treated with LiOH (2 eq, 2.0 N aqueous).After most starting material is consumed, the mixture is then dilutedwith ethyl acetate, washed with saturated ammonium chloride, water andbrine, dried over anhydrous MgSO₄ and filtered. The crude product isrecrystallized from hot ethanol to give compound 43.5.

e) A solution of 43.5, 43.2 (1.1 eq) and EDC (1.0 eq) in DMF is stirredfor 10 hours at room temperature. The mixture is then diluted with ethylacetate, washed with saturated ammonium chloride, water and brine, driedover anhydrous MgSO₄ and filtered. The crude product is then refluxedwith formic acid until LC-MS indicates the reaction is completed.Solvent is evaporated, and the crude product is purified by silica gelcolumn to give compound 43.6.

f) A mixture of 43.6 LiI (3 eq) in pyridine is reflux overnight. Thesolvent is removed and the residue is dissolved in EtOAc. The resultingsolution is then washed with saturated aqueous NH₄Cl and dried withanhydrous Na₂SO₄. The solvent is removed and the residue is dried invacuo to give a quantitative yield of compound 43.7. The crude productwas carried on the next step without further purification.

g) Compound 43 is made according to the procedure for the preparation ofcompound 3 except that compounds 43.7 and 40.6 are used instead of 3.4and 3.7.

Diversification

It will also be appreciated that each of the components used in thesynthesis of inventive compounds can be diversified either beforesynthesis or alternatively after the construction of the core structureof formula (I). As used herein, the term “diversifying” or “diversify”means reacting an inventive compound (I) or any of the precursorfragments (or any classes or subclasses thereof) at one or more reactivesites to modify a functional moiety or to add a functional moiety (e.g.,nucleophilic addition of a substrate). Described generally herein are avariety of schemes to assist the reader in the synthesis of a variety ofcompounds, either by diversification of the intermediate components orby diversification of the core structures as described herein, andclasses and subclasses thereof. It will be appreciated that a variety ofdiversification reactions can be employed to generate compounds otherthan those described in the Exemplification herein. As but a fewexamples, where a double bond is present in the compound structure,epoxidation and aziridation can be conducted to generate epoxide andaziridine derivatives of compounds described herein. For additionalguidance available in the art, the practitioner is directed to “AdvancedOrganic Chemistry”, March, J. John Wiley & Sons, 2001, 5^(th) ed., theentire contents of which are hereby incorporated by reference.

2) Biological Data:

As discussed above, LFA-ICAM interactions have been directly implicatedin numerous inflammatory disease states including, but not limited tograft rejection, dermatitis, psoriasis, asthma and rheumatoid arthritis.Thus, compounds capable of modulating adhesion between intracellularadhesion molecules (e.g., ICAM-1, -2 and -3) and the leukocyte integrinfamily of receptors would be useful in the development of noveltherapeutics. Described below are certain assays used for thedetermination of ICAM-1:LFA Receptor binding, Human T-Cell Adhesion, andT-Cell proliferation which are described in published PCT applicationsWO 99/49856 and WO 02/05114, the entire contents of which are herebyincorporated by reference. WO 99/49856 also describes the preparationand purification of full-length LFA-1 from 293 cells, the preparation ofa plasmid for expression of a human ICAM-1 immunoadhesion, and thegeneration of ICAM-1 immunoadhesion expressing 293 cell line.

ICAM-1:LFA Receptor Binding Assay (Protein/Protein Assay):

Competitive inhibition of the CD11a/CD18-ICAM-1 interaction isquantitated by adding known amounts of inhibitors according to the twoprotein/protein assay systems described below:

Forward Format LFA-1.ICAM-1 Assay (PPFF):

Purified full length recombinant human LFA-1 protein is diluted to 2.5μg/ml in 0.02 M Hepes, 0.15M NaCl, and 1 mM MnCl₂ and 96-well plates (50μl/well) are coated overnight at 4° C. The plates are washed with washbuffer (0.05% Tween in PBS) and blocked for 1 h at room temperature with1% BSA in 0.02M Hepes, 0.15 M NaCl, and 1 mM MnCl₂. Plates are washed.50 μl/well inhibitors, appropriately diluted in assay buffer (0.5% BSAin 0.02M Hepes, 0.15M NaCl, and 1 mM MnCl₂), are added to a 2× finalconcentration and incubated for 1 h at room temperature. 50 μl/well ofpurified recombinant human 5 domain ICAM-Ig, diluted to 50 ng/ml inassay buffer, is added and incubated 2 h at room temperature. Plates arewashed and bound ICAM-Ig is detected with Goat anti-HuIgG(Fc)-HRP for 1h at room temperature. Plates are washed and developed with 100 μl/wellTMB substrate for 10-30′ at room temperature. Colorimetric developmentis stopped with 100 μl/well 1M H₂PO₄ and read at 450 nM on aplatereader.

An alternative protein/protein assay system below also quantitatescompetitive inhibition of the CD11a/CD18-ICAM-1 interaction.

PLM2 Antibody Capture LFA-1:ICAM-1 Assay (PLM2)

A non-function blocking monoclonal antibody against human CD18, PLM-2(as described by Hildreth, et al., Molecular Immunology, Vol. 26, No. 9,pp. 883-895, 1989), is diluted to 5 μg/ml in PBS and 96-wellflat-bottomed plates are coated with 100 μl/well overnight at 4° C. Theplates are blocked with 0.5% BSA in assay buffer (0.02 M Hepes, 0.15 MNaCl, and 1 mM MnCl₂) 1 h at room temperature. Plates are washed with 50mM Tris pH 7.5, 0.1M NaCl, 0.05% Tween 20 and 1 mM MnCl₂. Purifiedfull-length recombinant human LFA-1 protein is diluted to 2 μg/ml inassay buffer and 100 ml/well is added to plates and incubated at 1 h at37° C. Plates are washed 3×. 50 μl/well inhibitors, appropriatelydiluted in assay buffer, are added to a 2× final concentration andincubated for 30′ at 37° C. 50 μl/well of purified recombinant human 5domain ICAM-Ig, diluted to 161 ng/ml (for a final concentration of 80ng/ml) in assay buffer, is added and incubated 2 h at 37° C. Plates arewashed and bound ICAM-Ig is detected with Goat anti-HuIgG(Fc)-HRP for 1h at room temperature. Plates are washed and developed with 100 μl/wellTMB substrate for 5-10′ at room temperature. Colorimetric development isstopped with 100 μl/well 1M H₃PO₄ and read at 450 nM on a platereader.

Human T-Cell Adhesion Assay (Cell Attachment Assay)

The T-cell adhesion assay is performed using a human T-lymphoid cellline HuT 78. Goat anti-HuIgG(Fc) is diluted to 2 μg/ml in PBS and96-well plates are coated with 50 μl/well at 37° C. for 1 h. Plates arewashed with PBS and blocked for 1 h at room temperature with 1% BSA inPBS. 5 domain ICAM-Ig is diluted to 100 ng/ml in PBS and 50 μl/well wasadded to the plates O/N at 4° C. HuT 78 cells are centrifuged at 100 gand the cell pellet is treated with 5 mM EDTA for ˜5′ at 37° C. in a 5%CO₂ incubator. Cells are washed in 0.14 M NaCl, 0.02 M Hepes, 0.2%glucose and 0.1 mM MnCl₂ (assay buffer) and centrifuged. The cells areresuspended in assay buffer to 3.0×10⁶c/ml. Inhibitors are diluted inassay buffer to a 2× final concentration and pre-incubated with HuT78cells for 30′ at room temperature. 100 μl/well of cells and inhibitorsare added to the plates and incubated at room temperature for 1 h. 100μl/well PBS is added and the plates are sealed and centrifuged invertedat 100 g for 5′. Unattached cells are flicked out of the plate andexcess PBS is blotted on a paper towel. 60 μl/well p-nitrophenyln-acetyl-β-D-glucosaminide (0.257 g to 100 ml citrate buffer) is addedto the plate and incubated for 1.5 h at 37° C. The enzyme reaction isstopped with 90 μl/well 50 mM glycine/5 mM EDTA and read on aplatereader at 405 nM. HUT 78 cell adhesion to 5dICAM-Ig is measuredusing the p-nitrophenyl n-acetyl-β-D-glucosaminide method of Landegren,U. (1984). J. Immunol. Methods 57, 379-388.

T-Cell Proliferation Assay:

This assay is an in vitro model of lymphocyte proliferation resultingfrom activation, induced by engagement of the T-cell receptor and LFA-1,upon interaction with antigen presenting cells (Springer, Nature 346:425 (1990)).

Microtiter plates (Nunc 96 well ELISA certified) are pre-coatedovernight at 4° C. with 50 μl of 2 μg/ml of goat anti-human Fc(CaltagH10700) and 50 μl of 0.07 μg/ml monoclonal antibody to CD3 (Immunotech0178) in sterile PBS. The next day coat solutions are aspirated. Platesare then washed twice with PBS and 100 μl of 17 ng/ml 5d-ICAM-1-IgG isadded for 4 hours at 37° C. Plates are washed twice with PBS prior toaddition of CD4+ T cells. Lymphocytes from peripheral blood areseparated from heparinized whole blood drawn from healthy donors. Analternative method is to obtain whole blood from healthy donors throughleukophoresis. Blood is diluted 1:1 with saline, layered and centrifugedat 2500×g for 30 minutes on LSM (6.2 g Ficoll and 9.4 g sodiumdiztrizoate per 100 ml) (Organon Technica, NJ). Monocytes are depletedusing a myeloid cell depletion reagent method (Myeloclear, CedarlaneLabs, Hornby, Ontario, Canada). PBLs are resuspended in 90%heat-inactivated Fetal Bovine serum and 10% DMSO, aliquoted, and storedin liquid nitrogen. After thawing, cells are resuspended in RPMI 1640medium (Gibco, Grand Island, N.Y.) supplemented with 10%heat-inactivated Fetal Bovine serum (Intergen, Purchase, N.Y.), 1 mMsodium pyruvate, 3 mM L-glutamine, 1 mM nonessential amino acids, 500μg/ml penicillin, 50 μg/ml streptomycin, 50 μg/ml gentamycin (Gibco).

Purification of CD4+ T cells are obtained by negative selection method(Human CD4 Cell Recovery Column Kit # CL110-5 Accurate). 100,000purified CD4+ T cells (90% purity) per microtiter plate well arecultured for 72 hours at 37° C. in 5% CO₂ in 100 ml of culture medium(RPMI 1640 (Gibco) supplemented with 10% heat inactivated FBS(Intergen), 0.1 mM non-essential amino acids, 1 nM Sodium Pyruvate, 100units/ml Penicillin, 100 μg/ml Streptomycin, 50 μg/ml Gentamicin, 10 mMHepes and 2 mM Glutamine) Inhibitors are added to the plate at theinitiation of culture. Proliferative responses in these cultures aremeasured by addition of 1 μCi/well titrated thymidine during the last 6hours before harvesting of cells. Incorporation of radioactive label ismeasured by liquid scintillation counting (Packard 96 well harvester andcounter). Results are expressed in counts per minute (cpm).

In Vitro Mixed Lymphocyte Culture Model:

The mixed lymphocyte culture model, which is an in vitro model oftransplantation (A. J. Cunningham, “Understanding Immunology,Transplantation Immunology” pages 157-159 (1978) examines the effects ofvarious LFA-1 antagonists in both the proliferative and effector arms ofthe human mixed lymphocyte response.

Isolation of Cells: Mononuclear cells from peripheral blood (PBMC) areseparated from heparanized whole blood drawn from healthy donors. Bloodis diluted 1:1 with saline, layered, and centrifuged at 2500×g for 30minutes on LSM (6.2 g Ficoll and 9.4 g sodium diztrizoate per 100 ml)(Organon Technica, NJ). An alternative method is to obtain whole bloodfrom healthy donors through leukophoresis. PBMCs are separated as above,resuspended in 90% heat inactivated Fetal Bovine serum and 10% DMSO,aliquoted and stored in liquid nitrogen. After thawing, cells areresuspended in RPMI 1640 medium (Gibco, Grand Island, N.Y.) supplementedwith 10% heat-inactivated Fetal Bovine serum (Intergen, Purchase, N.Y.),1 mM sodium pyruvate, 3 mM L-glutamine, 1 mM nonessential amino acids,500 μg/ml penicillin, 50 μg/ml streptomycin, 50 μg/ml gentamycin(Gibco).

Mixed Lymphocyte Response (MLR): One way human mixed lymphocyte culturesare established are in 96-well flat-bottomed microtiter plates. 1.5×10⁵responder PBMCs are co-cultured with an equal number of allogeneicirradiated (3000 rads for 3 minutes, 52 seconds stimulator PBMSc in 200μl of complete medium. LFA-1 antagonists are added at the initiation ofcultures. Cultures are incubated at 37° C. in 5% CO₂ for 6 days, thenpulsed with 1 μCi/well of 3H-thymidine (6.7 Ci/mmol, NEN, Boston, Mass.)for 6 hours. Cultures are harvested on a Packard cell harvester(Packard, Canberra, Canada). [³H] TdR incorporation is measured byliquid scintillation counting. Results are expressed as counts perminute (cpm).

1. A compound of the following structure:

or pharmaceutically acceptable salts thereof; wherein—C(═O)NHC(R¹)(R²)R³ is a moiety having the following structure:

R^(3A) is hydrogen; R^(S) is hydrogen; Ar₂ is:

s is an integer of 1; each occurrence of R^(P1) is independentlyhydrogen, halogen, or -GR^(G1), wherein G is —SO₂—, or —SO₂NR^(G2)—; andR^(G1) and R^(G2) are independently hydrogen, an aliphatic, alicyclic,heteroaliphatic, heterocyclic, aromatic or heteroaromatic moiety;R^(B1), R^(B2) and R^(E) are hydrogen; R^(4A) and R^(4B) are each Cl; Lis C═O; and AR₁ is


2. The compound of claim 1, wherein R^(P1) is selected from the groupconsisting of halogen and -GR^(G1), wherein G is —SO₂— and R^(G1) ismethyl.
 3. The compound of claim 2, wherein AR₁ is

and R^(P1) is selected from the group consisting of F and SO₂CH₃.
 4. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier or diluent.